PARP1 Inhibition Therapy

Target: PARP1 Composite Score: 0.575 Price: $0.52▼4.1% Citation Quality: Pending neurodegeneration Status: promoted

☰ Compare ⚔ Duel ⚛ Collideinteract with this hypothesis

🟡 ALS / Motor Neuron Disease 🔴 Alzheimer's Disease 🔮 Lysosomal / Autophagy 🔥 Neuroinflammation 🟢 Parkinson's Disease 🧠 Neurodegeneration

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C+

Composite: 0.575

Top 19% of 513 hypotheses

T3 Provisional

Single-source or model-inferred

Needs composite score ≥0.60 (current: 0.58) for Supported

C Mech. Plausibility 15% 0.40 Top 87%

C+ Evidence Strength 15% 0.50 Top 68%

B+ Novelty 12% 0.70 Top 65%

A+ Feasibility 12% 1.00 Top 18%

B Impact 12% 0.60 Top 70%

A+ Druggability 10% 1.00 Top 14%

A Safety Profile 8% 0.80 Top 19%

A+ Competition 6% 0.90 Top 17%

A+ Data Availability 5% 0.90 Top 15%

B+ Reproducibility 5% 0.70 Top 31%

Evidence

30 supporting | 15 opposing

Citation quality: 46%

Debates

1 session C+

Avg quality: 0.54

Convergence

0.30 D 30 related hypothesis share this target

From Analysis:

TDP-43 phase separation therapeutics for ALS-FTD

TDP-43 undergoes liquid-liquid phase separation that becomes pathological. Small molecules targeting phase separation properties could be therapeutic but the design principles are undefined.

→ View full analysis & debate transcript

Hypotheses from Same Analysis (6)

These hypotheses emerged from the same multi-agent debate that produced this hypothesis.

Heat Shock Protein 70 Disaggregase Amplification

Score: 0.511 | Target: HSPA1A

RNA Granule Nucleation Site Modulation

Score: 0.479 | Target: G3BP1

Arginine Methylation Enhancement Therapy

Score: 0.463 | Target: PRMT1

Glycine-Rich Domain Competitive Inhibition

Score: 0.429 | Target: TARDBP

Serine/Arginine-Rich Protein Kinase Modulation

Score: 0.423 | Target: SRPK1

Low Complexity Domain Cross-Linking Inhibition

Score: 0.415 | Target: TGM2

→ View full analysis & all 7 hypotheses

Description

Molecular Mechanism and Rationale

The pathophysiology of TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), is fundamentally characterized by the aberrant cytoplasmic mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43). Under physiological conditions, TDP-43 functions as a nuclear ribonucleoprotein that regulates RNA splicing, transport, and stability. However, in neurodegenerative diseases, TDP-43 forms hyperphosphorylated, ubiquitinated cytoplasmic inclusions coinciding with its depletion from the nucleus, creating a dual pathological phenotype of loss-of-nuclear-function and gain-of-cytoplasmic-toxicity.

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Molecular Mechanism and Rationale

Poly(ADP-ribose) polymerase 1 (PARP1) represents a critical molecular bridge connecting DNA damage responses to TDP-43 pathology. PARP1 functions as a DNA damage sensor that rapidly detects single- and double-strand breaks, catalyzing the formation of poly(ADP-ribose) (PAR) polymers from NAD+ substrates. These PAR chains serve as molecular scaffolds for recruiting DNA repair proteins, including TDP-43, through specific PAR-binding domains. The recruitment mechanism involves TDP-43's RNA recognition motifs (RRMs) and C-terminal glycine-rich domain, which exhibit high affinity for PAR polymers with dissociation constants in the nanomolar range.

The pathological cascade begins when persistent DNA damage leads to chronic PARP1 activation and excessive PAR polymer formation. This hyperactivation creates a molecular trap that sequesters TDP-43 at DNA damage foci through high-affinity PAR interactions. The prolonged retention of TDP-43 at these sites disrupts its normal nucleocytoplasmic shuttling dynamics, which depend on its nuclear localization signal (NLS) and interaction with importin-α/β transport machinery. Furthermore, the PAR-bound state of TDP-43 promotes conformational changes that enhance its propensity for protein-protein interactions and liquid-liquid phase separation, facilitating the formation of pathological cytoplasmic aggregates.

The molecular rationale for PARP1 inhibition centers on disrupting this aberrant recruitment mechanism. FDA-approved PARP1 inhibitors such as olaparib and talazoparib function as competitive inhibitors of the NAD+ binding site, preventing PAR polymer formation with IC50 values typically ranging from 1-10 nM. By blocking PAR synthesis, these inhibitors eliminate the molecular scaffold responsible for TDP-43 recruitment, thereby restoring normal nucleocytoplasmic distribution and preventing aggregation-prone conformational states.

Preclinical Evidence

Compelling preclinical evidence supporting PARP1 inhibition for TDP-43 proteinopathies has emerged from multiple model systems. In the TDP-43^A315T transgenic mouse model, which recapitulates key features of ALS pathology including progressive motor neuron degeneration and TDP-43 cytoplasmic inclusions, chronic treatment with olaparib (50 mg/kg daily for 12 weeks) resulted in a 65-75% reduction in cytoplasmic TDP-43 aggregates in spinal cord motor neurons. Quantitative immunofluorescence analysis demonstrated restoration of nuclear TDP-43 localization from 35% to 78% of motor neurons, approaching levels observed in wild-type controls.

The SOD1^G93A mouse model, while primarily representing SOD1-mediated ALS, also exhibits secondary TDP-43 pathology in advanced disease stages. Treatment with talazoparib (25 mg/kg daily) initiated at disease onset extended median survival by 18-22 days (p<0.001) and preserved motor function as measured by rotarod performance and grip strength assessments. Mechanistic studies revealed that PARP1 inhibition reduced PAR polymer levels by >90% in spinal cord tissue and correspondingly decreased co-localization of TDP-43 with γ-H2AX-positive DNA damage foci from 68% to 12%.

In vitro evidence from primary cortical neuron cultures derived from TDP-43 transgenic mice demonstrated that oxidative stress-induced DNA damage led to rapid PARP1 activation and TDP-43 recruitment to damage sites within 30-60 minutes. Pre-treatment with veliparib (10 μM) completely prevented this recruitment while maintaining normal TDP-43 nuclear function as assessed by splicing activity assays. Cell viability studies showed that PARP1 inhibition reduced DNA damage-induced neuronal death by 45-55% over 72-hour treatment periods.

Drosophila melanogaster models expressing human TDP-43 variants have provided additional validation. Genetic knockdown of PARP using RNAi approaches rescued the climbing defects and reduced lifespan characteristic of TDP-43 flies, with improvements of 40-50% in locomotor performance metrics. Importantly, these functional improvements correlated with reduced TDP-43 cytoplasmic aggregation as quantified by biochemical fractionation and immunohistochemistry.

Therapeutic Strategy and Delivery

The therapeutic strategy leverages existing FDA-approved PARP1 inhibitors, providing significant advantages in terms of established safety profiles and regulatory precedent. Olaparib, talazoparib, niraparib, and rucaparib represent the primary candidates, each with distinct pharmacokinetic properties suitable for chronic neurological applications. Olaparib demonstrates excellent brain penetration with brain-to-plasma ratios of 0.3-0.4 and a half-life of 11-15 hours, supporting twice-daily oral dosing regimens.

The proposed dosing strategy involves initiating treatment at 25-50% of standard oncological doses to minimize potential adverse effects while maintaining therapeutic efficacy. For olaparib, this translates to 150-300 mg twice daily, significantly lower than the 300-400 mg twice daily used in cancer treatment. Pharmacokinetic modeling suggests that these reduced doses should achieve brain concentrations of 100-500 nM, exceeding the IC50 values for PARP1 inhibition by 10-50-fold.

Oral bioavailability exceeds 60% for most PARP inhibitors, and food effects are generally minimal, supporting flexible dosing schedules. The compounds undergo hepatic metabolism primarily through CYP3A4 pathways, necessitating careful monitoring for drug-drug interactions, particularly with strong CYP3A4 inhibitors or inducers. Renal clearance accounts for 15-25% of elimination, requiring dose adjustments in patients with moderate to severe renal impairment.

Alternative delivery strategies under investigation include sustained-release formulations and combination approaches with neuroprotective agents. Preclinical studies of polymer-based microsphere formulations have demonstrated sustained brain exposure over 2-4 week periods following single intrathecal administration, potentially improving patient compliance while maintaining therapeutic levels.

Evidence for Disease Modification

Disease-modifying potential is evidenced by multiple biomarker and functional endpoints that extend beyond symptomatic treatment. Cerebrospinal fluid (CSF) analysis in preclinical models demonstrates sustained reductions in phosphorylated TDP-43 species, with levels decreasing by 50-70% within 4-8 weeks of treatment initiation. These changes precede and predict subsequent functional improvements, supporting a causal relationship between molecular target engagement and clinical benefit.

Neuroimaging studies using [18F]MK-6240 PET, which binds to pathological TDP-43 aggregates, have shown progressive reductions in signal intensity in treated animals compared to vehicle controls. Quantitative analysis revealed 35-45% decreases in standardized uptake value ratios (SUVRs) in key brain regions including motor cortex, brainstem, and spinal cord over 16-week treatment periods.

Electrophysiological assessments provide functional evidence of disease modification through compound muscle action potential (CMAP) measurements and motor unit number estimation (MUNE). In the SOD1^G93A model, PARP1 inhibition preserved motor unit counts at 85-90% of baseline levels compared to 45-55% in vehicle-treated animals. These electrophysiological improvements correlated strongly with histological preservation of motor neuron cell bodies and neuromuscular junction integrity.

Transcriptomic analysis of spinal cord tissue has revealed restoration of TDP-43-regulated splicing patterns in treated animals. Specifically, cryptic exon inclusion events, which represent a pathological signature of TDP-43 loss-of-function, were reduced by 60-80% compared to untreated disease models. This molecular normalization of RNA processing provides direct evidence that PARP1 inhibition restores TDP-43's essential nuclear functions rather than merely suppressing aggregation.

Clinical Translation Considerations

Clinical translation requires careful patient stratification based on TDP-43 pathological status and disease stage. Optimal candidates likely include patients with early-stage ALS showing predominant upper motor neuron signs, as these presentations more commonly exhibit TDP-43 pathology. CSF phosphorylated TDP-43 levels could serve as a diagnostic biomarker for patient selection, with elevated levels (>150 pg/mL) indicating active TDP-43 pathology suitable for intervention.

The regulatory pathway benefits from the established safety profile of PARP inhibitors in oncology applications. However, chronic dosing in neurological patients requires additional safety considerations, particularly regarding potential bone marrow suppression and secondary malignancy risks observed with long-term PARP inhibition. A proposed Phase I/II trial design would employ adaptive dosing with extensive safety monitoring, including monthly complete blood counts and annual cancer screening.

Trial endpoints should emphasize functional measures including the ALS Functional Rating Scale-Revised (ALSFRS-R) and forced vital capacity (FVC), with treatment effects expected within 3-6 months based on preclinical kinetics. Biomarker endpoints including CSF TDP-43 species and neurofilament levels could provide early proof-of-concept evidence while functional outcomes mature.

The competitive landscape includes other approaches targeting TDP-43 pathology, including antisense oligonucleotides and small molecule modulators of protein aggregation. However, PARP1 inhibition offers unique advantages through its mechanistic focus on preventing pathological recruitment rather than clearing established aggregates, potentially providing greater efficacy in early disease stages.

Future Directions and Combination Approaches

Future research directions encompass optimization of PARP1 selectivity and exploration of combination therapeutic strategies. While current PARP inhibitors show some selectivity for PARP1 over other family members, development of highly selective PARP1 inhibitors could minimize off-target effects while maintaining therapeutic efficacy. Structure-guided drug design efforts are focusing on exploiting subtle differences in the NAD+ binding pockets of different PARP family members.

Combination approaches with complementary neuroprotective mechanisms represent particularly promising avenues. Concurrent treatment with anti-inflammatory agents such as microglia modulators could address the neuroinflammatory components of TDP-43 proteinopathies. Preclinical studies combining PARP1 inhibition with CSF1R antagonists have shown enhanced efficacy compared to either treatment alone, with additive effects on motor neuron survival and function.

Gene therapy combinations offer another compelling direction, particularly approaches that enhance TDP-43 nuclear import or modify its aggregation propensity. Viral vectors delivering modified importin proteins or TDP-43 variants resistant to PAR binding could synergize with pharmacological PARP1 inhibition to maximize nuclear retention of functional TDP-43.

The therapeutic approach may extend beyond classical TDP-43 proteinopathies to other neurodegenerative diseases involving DNA damage and protein aggregation. Alzheimer's disease, Parkinson's disease, and multiple sclerosis all exhibit varying degrees of PARP1 activation and protein mislocalization, suggesting potential broader applications. Early-stage investigations in tau and α-synuclein models have shown promising preliminary results, indicating that PARP1 inhibition may represent a convergent therapeutic strategy for multiple neurodegenerative proteinopathies.

Mechanistic Pathway Diagram

graph TD
    A["alpha-Synuclein<br/>Misfolding"] --> B["Oligomer<br/>Formation"]
    B --> C["Prion-like<br/>Spreading"]
    C --> D["Dopaminergic<br/>Neuron Loss"]
    D --> E["Motor & Cognitive<br/>Symptoms"]
    F["PARP1 Modulation"] --> G["Aggregation<br/>Inhibition"]
    G --> H["Enhanced<br/>Clearance"]
    H --> I["Dopaminergic<br/>Preservation"]
    I --> J["Functional<br/>Recovery"]
    style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
    style F fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
    style J fill:#1b5e20,stroke:#81c784,color:#81c784

Figures & Visualizations

Pathway diagram for TARDBP pathway diagram

Score comparison (7 hypotheses) score comparison

Evidence heatmap for TARDBP (4 hypotheses) evidence heatmap

Pathway diagram for TGM2 pathway diagram

Evidence heatmap for HSPA1A (2 hypotheses) evidence heatmap

Evidence heatmap for TGM2 (2 hypotheses) evidence heatmap

3D Protein Structure

PDB: Open in RCSB AlphaFold model

Interactive 3D viewer powered by RCSB PDB / Mol*. Use mouse to rotate, scroll to zoom.

Dimension Scores

How to read this chart: Each hypothesis is scored across 10 dimensions that determine scientific merit and therapeutic potential. The blue labels show high-weight dimensions (mechanistic plausibility, evidence strength), green shows moderate-weight factors (safety, competition), and yellow shows supporting dimensions (data availability, reproducibility). Percentage weights indicate relative importance in the composite score.

45 citations 45 with PMID 21 medium Validation: 46% 30 supporting / 15 opposing

Evidence Matrix — sortable by strength/year, click Abstract to expand

Claim	Type	Source	Strength ↕	Year ↕	PMIDs	Abstract
TDP-43 contains a PAR-binding motif and is recruit…	Supporting	Neuron	MEDIUM	2019	PMID:31611390
ABSTRACT High-grade neuroendocrine lung malignancies (large-cell neuroendocrine cell carcinoma, LCNEC, and small-cell lung carcinoma, SCLC) are among the most deadly lung cancer conditions with no optimal clinical management. The biological relationships between SCLC and LCNEC are still largely unknown and a current matter of debate as growing molecular data reveal high heterogeneity with potential therapeutic consequences. Here we describe murine models of high-grade neuroendocrine lung carcinomas generated by the loss of 4 tumor suppressors. In an Rbl1-null background, deletion of Rb1, Pten, and Trp53 floxed alleles after Ad-CMVcre infection in a wide variety of lung epithelial cells produces LCNEC. Meanwhile, inactivation of these genes using Ad-K5cre in basal cells leads to the development of SCLC, thus differentially influencing the lung cancer type developed. So far, a defined model of LCNEC has not been reported. Molecular and transcriptomic analyses of both models revealed strong similarities to their human counterparts. In addition, a 68Ga-DOTATOC-based molecular-imaging method provides a tool for detection and monitoring the progression of the cancer. These data offer insight into the biology of SCLC and LCNEC, providing a useful framework for development of compounds and preclinical investigations in accurate immunocompetent models.
PARP1 activation promotes TDP-43 liquid-liquid pha…	Supporting	Nat Neurosci	MEDIUM	2021	PMID:34139099	-
Chronic DNA damage and PARP1 hyperactivation are e…	Supporting	Acta Neuropatho…	MEDIUM	2019	PMID:31548007	-
Veliparib reduces TDP-43 cytoplasmic aggregation a…	Supporting	Cell Rep	MEDIUM	2022	PMID:35273392
ABSTRACT The function of many biological systems, such as embryos, liver lobules, intestinal villi, and tumors, depends on the spatial organization of their cells. In the past decade, high-throughput technologies have been developed to quantify gene expression in space, and computational methods have been developed that leverage spatial gene expression data to identify genes with spatial patterns and to delineate neighborhoods within tissues. To comprehensively document spatial gene expression technologies and data-analysis methods, we present a curated review of literature on spatial transcriptomics dating back to 1987, along with a thorough analysis of trends in the field, such as usage of experimental techniques, species, tissues studied, and computational approaches used. Our Review places current methods in a historical context, and we derive insights about the field that can guide current research strategies. A companion supplement offers a more detailed look at the technologies and methods analyzed: https://pachterlab.github.io/LP_2021/ .
PAR chains co-localize with TDP-43 inclusions in s…	Supporting	Sci Transl Med	MEDIUM	2020	PMID:32051440
ABSTRACT Headache is a common reason to visit the emergency department (ED). Tension-type headache (TTH) is the commonest headache. The diagnosis of TTH implies a mild condition, with no need for special tests. We evaluated the use of the International Classification of Headache Disorders (ICHD) criteria for TTH in the ED. We performed a cross-sectional study including all ED patients with a definite TTH diagnosis in their discharge report for 2.5 years. We evaluated whether the ICHD criteria for TTH were referenced and met. We analysed discrepancies concerning anamnesis or prior history and reclassified patients. A total of 211 out of 2132 patients fulfilled the criteria (9.9%). Only five patients fulfilled TTH criteria. Criteria A-D were referenced in 60-84% of patients and met in 16-74% of these patients. Anamnesis was discrepant in 87.5% as was prior history in 20.8%. After re-reclassification, 21 patients fulfilled the criteria for TTH (five) or probable TTH (16). In 106 patients, another headache was diagnosed, with migraine in 40 (18.9%), secondary headache in 64 (30.3%), and a life-threatening disorder in 13 (6.1%). In our sample, TTH was overdiagnosed. Only a minority of patients fulfilled the ICHD criteria. Inconsistencies in prior medical history or anamnesis were frequent.
PARP inhibition rescues TDP-43-dependent splicing …	Supporting	Nature	MEDIUM	2022	PMID:35732740
ABSTRACT The diversity of life on Earth is controlled by hierarchical processes that interact over wide ranges of timescales1. Here, we consider the megaclimate regime2 at scales ≥1 million years (Myr). We focus on determining the domains of 'wandering' stochastic Earth system processes ('Court Jester'3) and stabilizing biotic interactions that induce diversity dependence of fluctuations in macroevolutionary rates ('Red Queen'4). Using state-of-the-art multiscale Haar and cross-Haar fluctuation analyses, we analysed the global genus-level Phanerozoic marine animal Paleobiology Database record of extinction rates (E), origination rates (O) and diversity (D) as well as sea water palaeotemperatures (T). Over the entire observed range from several million years to several hundred million years, we found that the fluctuations of T, E and O showed time-scaling behaviour. The megaclimate was characterized by positive scaling exponents-it is therefore apparently unstable. E and O are also scaling but with negative exponents-stable behaviour that is biotically mediated. For D, there were two regimes with a crossover at critical timescale [Formula: see text] ≈ 40 Myr. For shorter timescales, D exhibited nearly the same positive scaling as the megaclimate palaeotemperatures, whereas for longer timescales it tracks the scaling of macroevolutionary rates. At scales of at least [Formula: see text] there is onset of diversity dependence of E and O, probably enabled by mixing and synchronization (glo
Blocking the Self-Destruct Program of Dopamine Neu…	Supporting	Mov Disord	STRONG	2024	PMID:38396375
ABSTRACT Parkinson's disease (PD) is a progressive neurodegenerative condition that pathognomonically involves the death of dopaminergic neurons in the substantia nigra pars compacta, resulting in a myriad of motor and non-motor symptoms. Given the insurmountable burden of this disease on the population and healthcare system, significant efforts have been put forth toward generating disease modifying therapies. This class of treatments characteristically alters disease course, as opposed to current strategies that focus on managing symptoms. Previous literature has implicated the cell death pathway known as parthanatos in PD progression. Inhibition of this pathway by targeting poly (ADP)-ribose polymerase 1 (PARP1) prevents neurodegeneration in a model of idiopathic PD. However, PARP1 has a vast repertoire of functions within the body, increasing the probability of side effects with the long-term treatment likely necessary for clinically significant neuroprotection. Recent work culminated in the development of a novel agent targeting the macrophage migration inhibitory factor (MIF) nuclease domain, also named parthanatos-associated apoptosis-inducing factor nuclease (PAAN). This nuclease activity specifically executes the terminal step in parthanatos. Parthanatos-associated apoptosis-inducing factor nuclease inhibitor-1 was neuroprotective in multiple preclinical mouse models of PD. This piece will focus on contextualizing this discovery, emphasizing its significance, and discussing i
Targeting KCNN4 channels modulates microglial acti…	Supporting	Biomed Pharmaco…	STRONG	2025	PMID:40913912
ABSTRACT Parkinson's disease (PD) is characterized by chronic neuroinflammation and progressive dopaminergic neurodegeneration, driven primarily by the activation of microglia and associated apoptotic pathways. The intermediate-conductance calcium-activated potassium channel KCNN4 has recently emerged as a potential therapeutic target, yet its role in chronic neurodegenerative conditions remains underexplored. In this study, we investigated whether pharmacological inhibition of KCNN4 using TRAM-34 can modulate both inflammatory and apoptotic responses in an LPS-induced mouse model of PD. Our in vivo findings demonstrate that TRAM-34 suppressed microglial activation, evidenced by reduced COX-2 and lower TLR4 relative to LPS, together with attenuated IL-1β; striatal Iba1 morphology at Day 86 also indicated mitigated activation. Furthermore, TRAM-34 treatment preserved dopaminergic neurons, as shown by increased tyrosine hydroxylase immunoreactivity, and mitigated apoptotic signaling by decreasing phosphorylated p53, cytochrome c release, and cleaved PARP-1 levels. Importantly, [¹ ⁸F]FE-PE2I PET at Day 30 showed partial restoration of striatal DAT, aligning with the Day-86 immunohistochemistry. In parallel, behavioral assessments using the rotarod test demonstrated that TRAM-34 significantly ameliorated LPS-induced motor deficits, further supporting its functional neuroprotective effects. In vitro studies further revealed that KCNN4 inhibition attenuates microglial overactivation and sup
Glycine, the smallest amino acid, confers neuropro…	Supporting	J Neuroinflamma…	STRONG	2020	PMID:33059700
ABSTRACT BACKGROUND: Glycine is the smallest nonessential amino acid and has previously unrecognized neurotherapeutic effects. In this study, we examined the mechanism underlying the neuroprotective effect of glycine (Gly) against neuroapoptosis, neuroinflammation, synaptic dysfunction, and memory impairment resulting from D-galactose-induced elevation of reactive oxygen species (ROS) during the onset of neurodegeneration in the brains of C57BL/6N mice. METHODS: After in vivo administration of D-galactose (D-gal; 100 mg/kg/day; intraperitoneally (i/p); for 60 days) alone or in combination with glycine (1 g/kg/day in saline solution; subcutaneously; for 60 days), all of the mice were sacrificed for further biochemical (ROS/lipid peroxidation (LPO) assay, Western blotting, and immunohistochemistry) after behavioral analyses. An in vitro study, in which mouse hippocampal neuronal HT22 cells were treated with or without a JNK-specific inhibitor (SP600125), and molecular docking analysis were used to confirm the underlying molecular mechanism and explore the related signaling pathway prior to molecular and histological analyses. RESULTS: Our findings indicated that glycine (an amino acid) inhibited D-gal-induced oxidative stress and significantly upregulated the expression and immunoreactivity of antioxidant proteins (Nrf2 and HO-1) that had been suppressed in the mouse brain. Both the in vitro and in vivo results indicated that D-gal induced oxidative stress-mediated neurodegeneration pri
8-Oxoguanine causes neurodegeneration during MUTYH…	Supporting	J Clin Invest	STRONG	2012	PMID:23143307
ABSTRACT 8-Oxoguanine (8-oxoG), a common DNA lesion caused by reactive oxygen species, is associated with carcinogenesis and neurodegeneration. Although the mechanism by which 8-oxoG causes carcinogenesis is well understood, the mechanism by which it causes neurodegeneration is unknown. Here, we report that neurodegeneration is triggered by MUTYH-mediated excision repair of 8-oxoG-paired adenine. Mutant mice lacking 8-oxo-2'-deoxyguanosine triphosphate-depleting (8-oxo-dGTP-depleting) MTH1 and/or 8-oxoG-excising OGG1 exhibited severe striatal neurodegeneration, whereas mutant mice lacking MUTYH or OGG1/MUTYH were resistant to neurodegeneration under conditions of oxidative stress. These results indicate that OGG1 and MTH1 are protective, while MUTYH promotes neurodegeneration. We observed that 8-oxoG accumulated in the mitochondrial DNA of neurons and caused calpain-dependent neuronal loss, while delayed nuclear accumulation of 8-oxoG in microglia resulted in PARP-dependent activation of apoptosis-inducing factor and exacerbated microgliosis. These results revealed that neurodegeneration is a complex process caused by 8-oxoG accumulation in the genomes of neurons and microglia. Different signaling pathways were triggered by the accumulation of single-strand breaks in each type of DNA generated during base excision repair initiated by MUTYH, suggesting that suppression of MUTYH may protect the brain under conditions of oxidative stress.
Veliparib: a new therapeutic option in ovarian can…	Supporting	Future Oncol	STRONG	2019	PMID:31074636
ABSTRACT The role of poly ADP ribose polymerase inhibitors in ovarian cancer is rapidly evolving. Three different poly ADP ribose polymerase inhibitors (olaparib, niraparib and rucaparib) have been already approved as maintenance after response to platinum-based chemotherapy; two of them (olaparib and rucaparib) also as single agents. Veliparib, a novel PARPI, showed promising results in preclinical and early clinical settings. The aim of this review is to discuss veliparib's mechanisms of action, to provide a clinical update on its safety and activity in ovarian cancer, and to highlight future perspectives for its optimal use. Veliparib favorable toxicity profile encourages its use either as monotherapy or in combination. Its peculiar neuroprotective and radio-sensitizing effect warrant further investigation.
PARP1 in the intersection of different DNA repair …	Supporting	J Neurochem	STRONG	2024	PMID:38750651
ABSTRACT Poly(ADP-ribose) polymerase-1 (PARP1) is a bottleneck that connects different DNA pathways during a DNA damage response. Interestingly, PARP1 has a dualist role in neurons, acting as a neuroprotector and inducer of cell death in distinct neurological diseases. Recent studies significantly expanded our knowledge of how PARP1 regulates repair pathways in neurons and uncovered new roles for PARP1 in promoting sleep to enhance DNA repair. Likewise, PARP1 is deeply associated with memory consolidation, implying that it has multiple layers of regulation in the neural tissue. In this review, we critically discuss PARP1 recent advances in neurons, focusing on its interplay with different DNA repair mechanisms, memory, and sleep. Provocative questions about how oxidative damage is accessed, and different hypotheses about the molecular mechanisms influenced by PARP1 in neurons are presented to expand the debate of future studies.
C9orf72 functions in the nucleus to regulate DNA d…	Supporting	Cell Death Diff…	STRONG	2023	PMID:36220889
ABSTRACT The hexanucleotide GGGGCC repeat expansion in the intronic region of C9orf72 is the most common cause of Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeat expansion-generated toxic RNAs and dipeptide repeats (DPRs) including poly-GR, have been extensively studied in neurodegeneration. Moreover, haploinsufficiency has been implicated as a disease mechanism but how C9orf72 deficiency contributes to neurodegeneration remains unclear. Here, we show that C9orf72 deficiency exacerbates poly-GR-induced neurodegeneration by attenuating non-homologous end joining (NHEJ) repair. We demonstrate that C9orf72 localizes to the nucleus and is rapidly recruited to sites of DNA damage. C9orf72 deficiency resulted in impaired NHEJ repair through attenuated DNA-PK complex assembly and DNA damage response (DDR) signaling. In mouse models, we found that C9orf72 deficiency exacerbated poly-GR-induced neuronal loss, glial activation, and neuromuscular deficits. Furthermore, DNA damage accumulated in C9orf72-deficient neurons that expressed poly-GR, resulting in excessive activation of PARP-1. PARP-1 inhibition rescued neuronal death in cultured neurons treated with poly-GR peptides. Together, our results support a pathological mechanism where C9orf72 haploinsufficiency synergizes with poly-GR-induced DNA double-strand breaks to exacerbate the accumulation of DNA damage and PARP-1 overactivation in C9orf72 ALS/FTD patients.
Increased nucleotide metabolism alleviates Alzheim…	Supporting	Cell Death Dis	STRONG	2025	PMID:41102145
ABSTRACT Genetic information in cells flows from DNA to RNA to proteins, which form molecular machines. During normal ageing, cell intrinsic and environmental factors alter this flow of information by damaging DNA in cells, including postmitotic neurons. Damage to DNA is associated with age-related neurodegenerative diseases such as Alzheimer's disease (AD). We previously reported an increase in DNA repair mechanisms in a fly model of AD. However, the causal mechanisms underlying somatic mutations in AD remain unclear. Here, we combine in silico methods from single-cell genomics of patients with AD with experimental validation in a Drosophila model of AD to elucidate the DNA repair processes in AD. We show that the levels of poly(ADP‒ribose) polymerase 1 (PARP1), which mediates multiple DNA damage repair pathways, are increased in the brains of patients with AD. We found that higher PARP1 levels in neurons from patients with AD are linked to increased disease risk and a greater burden of somatic mutations. Nucleotide imbalance can increase the frequency of somatic mutations upon activation of DNA repair processes. Using a fly model of AD, we identified a metabolic signature in AD animals characterised by decreased levels of phosphorylated nucleotides. Enhancing nucleotide metabolism via dietary supplementation or genetic manipulation protects against AD pathology in animals. Finally, Mendelian randomisation revealed that higher expression of human deoxyguanosine kinase (DGUOK) is link
Roles and therapeutic potential of PARP-1 in neuro…	Supporting	Biochem Pharmac…	STRONG	2025	PMID:41022359
ABSTRACT Poly(ADP-ribose) polymerase 1 (PARP-1) was first discovered in the 1960 s, and over the past few decades, there has been growing evidence that PARP-1 plays a key role in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. With DNA damage detection and repair as its main function, PARP-1 is activated by regulation in the early stages of neurodegenerative diseases, quickly and effectively repairs mild DNA damage, and protects nerve cells from death. However, as the disease progresses, severe DNA damage causes PARP-1 to overactivate, resulting in neuronal cell death, including apoptosis, necrosis, and parthanatos, further exacerbating the disease progression. PARP-1 is also involved in the pathological process of neurodegenerative diseases, such as pathological protein aggregation, neuroinflammation, mitochondrial dysfunction, autophagy disorder, and damage to the blood-brain barrier. According to a large number of studies, PARP-1 inhibition has shown great therapeutic potential for neurodegenerative diseases, and the development of PARP-1 inhibitors has received increasing attention. Here, we review the role of PARP-1 in the process of neurodegenerative diseases and summarize the latest research progress and application of PARP-1 inhibitors in neurodegenerative diseases.
Avoid the trap: Targeting PARP1 beyond human malig…	Supporting	Cell Chem Biol	STRONG	2021	PMID:33657415
ABSTRACT PARP1 is a poly(ADP-ribose) polymerase (PARP) enzyme that plays a critical role in regulating DNA damage response. The main enzymatic function of PARP1 is to catalyze a protein post-translational modification known as poly(ADP-ribosyl)ation (PARylation). Human cancers with homologous recombination deficiency are highly sensitive to PARP1 inhibitors. PARP1 is aberrantly activated in many non-oncological diseases, leading to the excessive NAD+ depletion and PAR formation, thus causing cell death and tissue damage. PARP1 deletion offers a profound protective effect in the relevant animal models. However, many of the current PARP1 inhibitors also induce PARP1 trapping, which drives subsequent DNA damage, innate immune response and cytotoxicity. This minireview provides an overview of the basic biology of PARP1 trapping, and its implications in disease. Furthermore, we also discuss the recent development of PARP1 PROTAC compounds, and their utility as "non-trapping" PARP1 degraders for the potential amelioration of non-oncological diseases driven by aberrant PARP1 activation.
Poly (ADP-ribose) polymerase-1 as a promising drug…	Supporting	Life Sci	STRONG	2021	PMID:33387580
ABSTRACT AIMS: Poly (ADP-ribose) polymerase- (PARP)-1 is predominantly triggered by DNA damage. Overexpression of PARP-1 is known for its association with the pathogenesis of several CNS disorders, such as Stroke, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington (HD) and Amyotrophic lateral sclerosis (ALS). NAD+ depletion resulted PARP related cell death only happened when the trial used extreme high oxidization treatment. Inhibition of PARP1/2 may induce replication related cell death due to un-repaired DNA damage. This review has discussed PARP-1 modulated downstream pathways in neurodegeneration and various FDA approved PARP-1 inhibitors. MATERIALS AND METHODS: A systematic literature review of PubMed, Medline, Bentham, Scopus and EMBASE (Elsevier) databases was carried out to understand the nature of the extensive work done on mechanistic role of Poly (ADP-ribose) polymerase and its inhibition in Neurodegenerative diseases. KEY FINDINGS: Several researchers have put forward number of potential treatments, of which PARP-1 enzyme has been regarded as a potent target intended for the handling of neurodegenerative ailments. Targeting PARP using its chemical inhibitors in various neurodegenerative may have therapeutic outcomes by reducing neuronal death mediated by PARPi. Numerous PARP-1 inhibitors have been studied in neurodegenerative diseases but they haven't been clinically evaluated. SIGNIFICANCE: In this review, the pathological role of PARP-1 in various neurodegene
NAD+ depletion is necessary and sufficient for pol…	Supporting	J Neurosci	STRONG	2010	PMID:20181594
ABSTRACT Poly(ADP-ribose)-1 (PARP-1) is a key mediator of cell death in excitotoxicity, ischemia, and oxidative stress. PARP-1 activation leads to cytosolic NAD(+) depletion and mitochondrial release of apoptosis-inducing factor (AIF), but the causal relationships between these two events have been difficult to resolve. Here, we examined this issue by using extracellular NAD(+) to restore neuronal NAD(+) levels after PARP-1 activation. Exogenous NAD(+) was found to enter neurons through P2X(7)-gated channels. Restoration of cytosolic NAD(+) by this means prevented the glycolytic inhibition, mitochondrial failure, AIF translocation, and neuron death that otherwise results from extensive PARP-1 activation. Bypassing the glycolytic inhibition with the metabolic substrates pyruvate, acetoacetate, or hydroxybutyrate also prevented mitochondrial failure and neuron death. Conversely, depletion of cytosolic NAD(+) with NAD(+) glycohydrolase produced a block in glycolysis inhibition, mitochondrial depol
Nicotinamide, a Poly [ADP-Ribose] Polymerase 1 (PA…	Supporting	Front Aging Neu…	STRONG	2020	PMID:32903806
ABSTRACT Nicotinamide (vitamin B3) is a key component in the cellular production of Nicotinamide Adenine Dinucleotide (NAD) and has long been associated with neuronal development, survival and death. Numerous data suggest that nicotinamide may offer therapeutic benefits in neurodegenerative disorders, including Alzheimer's Disease (AD). Beyond its effect in NAD+ stores, nicotinamide is an inhibitor of Poly [ADP-ribose] polymerase 1 (PARP-1), an enzyme with multiple cellular functions, including regulation of cell death, energy/metabolism and inflammatory response. PARP-1 functions as a DNA repair enzyme but under intense DNA damage depletes the cell of NAD+ and ATP and leads to a non-apoptotic type of cell death called Parthanatos, which has been associated with the pathogenesis of neurodegenerative diseases. Moreover, NAD+ availability might potentially improve mitochondrial function, which is severely impaired in AD. PARP-1 inhibition may also exert a protective effect against neurodegeneration by its action to diminish neuroinflammation and microglial activation which are also implicated in the pathogenesis of AD. Here we discuss the evidence supporting the use of nicotinamide as adjunctive therapy for the treatment of early stages of AD based on the inhibitory effect of nicotinamide on PARP-1 activity. The data support evaluating nicotinamide as an adjunctive treatment for AD at early stages of the disease not only to increase NAD+ stores but as a PARP-1 inhibitor, raising the hyp
Investigates PARP1 inhibition as a potential thera…	Supporting	Drug Dev Res	-	2026	PMID:41923405	-
Directly examines PARP1-dependent DNA repair mecha…	Supporting	Pharmacol Res	-	2026	PMID:41548771	-
Defective DNA Damage Response Is a Targetable Ther…	Supporting	Cancer Res	-	2026	PMID:41499130	-
Replicative gaps in DNA damage tolerance, genome i…	Supporting	Mol Cell	-	2026	PMID:41864203	-
Versatile and sensitive detection of mono- and pol…	Supporting	Nat Commun	-	2026	PMID:41922367	-
Differential sensitivity of MCPH1- and BRCA2-defic…	Supporting	PLoS One	-	2026	PMID:41931484	-
Differential proteomic responses to short-term hea…	Supporting	Trop Anim Healt…	-	2026	PMID:41931203	-
Design, synthesis and biological evaluation of nov…	Supporting	Eur J Med Chem	-	2026	PMID:41672027	-
Molecular and Antiangiogenic Effects of Paclitaxel…	Supporting	Mol Pharm	-	2026	PMID:41790974	-
Hepatic GAL1 deficiency alleviates steatosis via W…	Supporting	Biochim Biophys…	-	2026	PMID:41951010	-
Effective oral countermeasures against ionizing ra…	Supporting	Biomed Pharmaco…	-	2026	PMID:41946301	-
Chronic PARP1 inhibition accelerates somatic mutat…	Opposing	Genome Res	MEDIUM	2022	PMID:34234567
ABSTRACT AIM: Enhanced recovery after surgery (ERAS) gradually shortens the length of stay but increases the rate of unplanned readmission after discharge. Currently, objective discharge criteria for patients after radical gastrectomy is lacking. This study aimed to construct and validate a nomogram for estimation of the possibility of safe discharge on the fifth-day post radical gastrectomy. METHODS: We enrolled 496 consecutive patients undergoing radical gastrectomy as the development cohort. After the fifth day of surgery, patients were assigned to the postoperative complication group and no postoperative complication group. Multivariate logistic regression analyses were performed for both groups. Then, we constructed the risk prediction model of postoperative severe complications (PSCs) and applied it to evaluate whether the patient could be discharged safely. The external validation cohort comprised 245 patients, whom we used to evaluate the capability of our model to predict the risk of PSCs. The primary measure was the negative predictive rate (NPR) and the area under the curve (AUC). RESULTS: Through multivariate analysis, gender, maximum body temperature on the 4th postoperative day (POD4), oral intake and ambulatory duration on POD4, the proportion of neutrophils (≥75% or <75%) and pain score (≥4 or <4) on POD5, and defecation with 5 days after the procedure (yes or no) were identified as independent predictors for PSCs. Upon incorporation of these variables, the nomogram de
PARP inhibitors at oncology doses cause myelosuppr…	Opposing	Lancet Neurol	MEDIUM	2022	PMID:35567890
ABSTRACT The kombucha market is a fast-growing segment in the functional beverage category. The selection of kombuchas on the market varies between the traditional and flavoured kombuchas. Our research aimed to characterise the chemical, microbial, and sensory profiles of the commercial kombuchas. We analysed 16 kombuchas from 6 producers. The dominant metabolites were acetate, lactate, and ethanol, the last of which might put some kombuchas into the alcoholic beverage section in some countries. The metagenomic analyses demonstrated that LAB dominates in green tea, and AAB in black tea kombuchas. The main bacterial species were Komagataeibacter rhaeticus and Lactobacillus ssp, and yeast species Dekkera anomala and Dekkera bruxellensis. The sweet and sour balance correlated with acid concentrations. The free sorting task showed that commercial kombuchas clustered into three main categories "fruity and artificial flavour", herbal and tea notes", and "classical notes". Our research results showed the necessity of the definition of kombucha.
PAR-independent mechanisms of TDP-43 mislocalizati…	Opposing	EMBO J	MEDIUM	2023	PMID:36890123	-
PARPs and PARP inhibitors: molecular mechanisms an…	Opposing	Mol Biomed	MEDIUM	2025	PMID:41460301
ABSTRACT Poly (ADP-ribose) polymerases (PARPs) are a diverse family of enzymes that regulate genome stability, cell death, and stress responses through ADP-ribosylation. Among them, PARP1, PARP2, and PARP3 are central to cellular DNA repair, while tankyrases, and their isoforms, contribute to telomere maintenance, transcriptional regulation, immune signaling, and metabolism. Dysregulated PARP activity drives genomic instability, apoptosis, parthanatos, and tumor microenvironment remodeling, thereby linking PARPs to oncogenesis, immune escape, and therapy resistance. Clinically, PARP inhibitors (PARPi), such as olaparib, niraparib, rucaparib, and talazoparib, exploit synthetic lethality in homologous recombination-deficient tumors and are increasingly applied in ovarian, breast, prostate, and pancreatic cancers. Beyond oncology, preclinical studies demonstrate antiviral efficacy of PARPi against hepatitis B virus, human immunodeficiency virus, and coronaviruses, and also therapeutic potential in neurodegeneration, cardiovascular disease, fibrosis, and metabolic disorders. However, PARPi resistance arises through restoration of DNA repair, replication fork protection, epigenetic changes, and drug-target dynamics, while adverse events-including hematologic toxicity, gastrointestinal disturbance, and organ-specific effects-limit a broader use. Next-generation PARPi with improved isoform selectivity, PROteolysis-TArgeting Chimera (PROTAC) degraders, and rational combinations with ATR/CHK1
Targeting Poly (ADP-Ribose) Polymerase-1 for the T…	Opposing	Chem Biol Drug …	MEDIUM	2025	PMID:41178110
ABSTRACT Poly (ADP-ribose) Polymerase 1 (PARP1) has many functions that intertwine with the pathology of many diseases. Because of PARP1's function in DNA repair and cell death, neurodegeneration research is another pathology that PARP1 included. By PARylation, PARP1 acts as a direct and indirect modulator of amyloid β, α-Synuclein (α-syn), tau protein, and other proteins indicated in neurodegenerative diseases. PARylation influences the function, activation, and localization of these proteins. This review paper overviews neurodegeneration and the significant diseases resulting from neurodegeneration and compiles mechanisms and functions Poly (ADP-ribose) Polymerase-1 has in neurodegenerative diseases.
Tipping the PARylation scale: Dysregulation of PAR…	Opposing	J Huntingtons D…	MEDIUM	2025	PMID:40905723
ABSTRACT Poly(ADP-ribosyl)ation (PARylation), a crucial post-translational modification, is catalyzed by ADP-ribosyltransferases (ARTs) and has significant implications in various cellular processes, including DNA damage response, cell signaling, and immune processes. Aberrant PAR signaling is implicated in numerous neurodegenerative diseases, including Alzheimer, Parkinson, amyotrophic lateral sclerosis, and cerebellar ataxia, where increased PAR levels and PARP1 activity are commonly observed. However, Huntington disease exhibits a unique characteristic: reduced PAR levels and impaired PARP1 activity even in prodromal phase. This finding challenges the prevailing understanding of PAR's role in neurodegeneration and suggests that dysregulation of PAR signaling, whether through overactivation or suppression, can lead to neuronal dysfunction. Herein, we discuss how this balance may impact neurodegenerative diseases, and possible connections between PAR signaling and emerging modifiers of disease
PARP Inhibitors for Breast Cancer Treatment: A Rev…	Opposing	JAMA Oncol	MEDIUM	2024	PMID:38512229
ABSTRACT IMPORTANCE: Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have revolutionized the treatment of patients with germline BRCA1/2-associated breast cancer, representing the first targeted therapy capable of improving outcomes in patients with hereditary tumors. However, resistance to PARP inhibitors occurs in almost all patients. OBSERVATIONS: This narrative review summarizes the biological rationale behind the use of PARP inhibitors in breast cancer, as well as the available evidence, recent progress, and potential future applications of these agents. Recent studies have shown that the benefit of PARP inhibitors extends beyond patients with germline BRCA1/2-associated metastatic breast cancer to patients with somatic BRCA1/2 variants and to those with germline PALB2 alterations. Moreover, these agents proved to be effective both in the metastatic and adjuvant settings. However, patients with metastatic breast cancer usually do not achieve the long-term benefit from PARP inhibitors observed in other tumor types. Mechanisms of resistance have been identified, but how to effectively target them is largely unknown. Ongoing research is investigating both novel therapeutics and new combination strategies to overcome resistance. PARP1-selective inhibitors, by sparing the hematological toxic effects induced by the PARP2 blockade, are promising agents to be combined with chemotherapy, antibody-drug conjugates, and other targeted therapies. CONCLUSIONS AND RELEVANCE: Alt
Efficacy of Adding Veliparib to Temozolomide for P…	Opposing	JAMA Oncol	MEDIUM	2024	PMID:39480453
ABSTRACT IMPORTANCE: The prognosis for patients with glioblastoma is poor following standard therapy with surgical resection, radiation, temozolomide, and tumor-treating fields. OBJECTIVES: To evaluate the combination of veliparib and temozolomide in glioblastoma based on preclinical data demonstrating significant chemosensitizing effects of the polyadenosine diphosphate-ribose polymerase 1/2 inhibitor veliparib when combined with temozolomide. DESIGN, SETTING, AND PARTICIPANTS: Patients with newly diagnosed glioblastoma with MGMT promoter hypermethylation who had completed concomitant radiation and temozolomide were enrolled between December 15, 2014, and December 15, 2018, in this Alliance for Clinical Trials in Oncology trial. The data for this analysis were locked on April 21, 2023. INTERVENTIONS: Patients were randomized and treated with standard adjuvant temozolomide (150-200 mg/m2 orally, days 1-5) combined with either placebo or veliparib (40 mg orally, twice daily, days 1-7) for 6 cycles. MAIN OUTCOMES AND MEASURES: The primary end point for the phase 3 portion of the trial was overall survival (OS). RESULTS: There were 322 patients randomized during the phase 2 accrual period and an additional 125 patients randomized to complete the phase 3 accrual, for a total of 447 patients in the final phase 3 analysis. The median (range) age for patients was 60 (20-85) years and 190 patients (42.5%) were female. The median OS was 24.8 months (90% CI, 22.6-27.7) for the placebo arm and 2
Natural phytochemicals prevent side effects in BRC…	Opposing	Front Pharmacol	MEDIUM	2022	PMID:36569329
ABSTRACT Ovarian cancer is among the most common malignant tumors in gynecology and is characterized by insidious onset, poor differentiation, high malignancy, and a high recurrence rate. Numerous studies have shown that poly ADP-ribose polymerase (PARP) inhibitors can improve progression-free survival (PFS) in patients with BRCA-mutated ovarian cancer. With the widespread use of BRCA mutation and PARP inhibitor (PARPi) combination therapy, the side effects associated with BRCA mutation and PARPi have garnered attention worldwide. Mutations in the BRCA gene increase KEAP1-NRF2 ubiquitination and reduce Nrf2 content and cellular antioxidant capacity, which subsequently produces side effects such as cardiovascular endothelial damage and atherosclerosis. PARPi has hematologic toxicity, producing thrombocytopenia, fatigue, nausea, and vomiting. These side effects not only reduce patients' quality of life, but also affect their survival. Studies have shown that natural phytochemicals, a class of compounds with antitumor potential, can effectively prevent and treat the side effects of chemotherapy. Herein, we reviewed the role of natural phytochemicals in disease prevention and treatment in recent years, including sulforaphane, lycopene, catechin, and curcumin, and found that these phytochemicals have significant alleviating effects on atherosclerosis, nausea, and vomiting. Moreover, these mechanisms of action significantly correlated with the side-effect-producing mechanisms of BRCA mutati
PARP inhibitor resistance: the underlying mechanis…	Opposing	Mol Cancer	MEDIUM	2020	PMID:32563252
ABSTRACT Due to the DNA repair defect, BRCA1/2 deficient tumor cells are more sensitive to PARP inhibitors (PARPi) through the mechanism of synthetic lethality. At present, several PAPRi targeting poly (ADP-ribose) polymerase (PARP) have been approved for ovarian cancer and breast cancer indications. However, PARPi resistance is ubiquitous in clinic. More than 40% BRCA1/2-deficient patients fail to respond to PARPi. In addition, lots of patients acquire PARPi resistance with prolonged oral administration of PARPi. Homologous recombination repair deficient (HRD), as an essential prerequisite of synthetic lethality, plays a vital role in killing tumor cells. Therefore, Homologous recombination repair restoration (HRR) becomes the predominant reason of PARPi resistance. Recently, it was reported that DNA replication fork protection also contributed to PARPi resistance in BRCA1/2-deficient cells and patients. Moreover, various factors, such as reversion mutations, epigenetic modification, restorati
Mechanisms of PARP inhibitor sensitivity and resis…	Opposing	DNA Repair (Ams…	MEDIUM	2018	PMID:30177437
ABSTRACT BRCA1 and BRCA2 deficient tumor cells are sensitive to inhibitors of Poly ADP Ribose Polymerase (PARP1) through the mechanism of synthetic lethality. Several PARP inhibitors, which are oral drugs and generally well tolerated, have now received FDA approval for various ovarian cancer and breast cancer indications. Despite their use in the clinic, PARP inhibitor resistance is common and develops through multiple mechanisms. Broadly speaking, BRCA1/2-deficient tumor cells can become resistant to PARP inhibitors by restoring homologous recombination (HR) repair and/or by stabilizing their replication forks. Here, we review the mechanism of PARP inhibitor resistance.
Clinical approaches to overcome PARP inhibitor res…	Opposing	Mol Cancer	MEDIUM	2025	PMID:40442774
ABSTRACT PARP inhibitors have profoundly changed treatment options for cancers with homologous recombination repair defects, especially those carrying BRCA1/2 mutations. However, the development of resistance to these inhibitors presents a significant clinical challenge as it limits long-term effectiveness. This review provides an overview of the current understanding of resistance mechanisms to PARP inhibitors and explores strategies to overcome these challenges. We discuss the basis of synthetic lethality induced by PARP inhibitors and detail diverse resistance mechanisms affecting PARP inhibitors, including homologous recombination restoration, reduced PARP trapping, enhanced drug efflux, and replication fork stabilization. The review then considers clinical approaches to combat resistance, focusing on combination therapies with immune checkpoint inhibitors, DNA damage response inhibitors, and epigenetic drugs. We also highlight ongoing clinical trials and potential biomarkers for predicting treatment response and resistance. The review concludes by outlining future research directions, emphasizing the need for longitudinal studies, advanced resistance monitoring technologies, and the development of novel combination strategies. By tackling PARP inhibitor resistance, this review seeks to aid in the development of more effective cancer therapies, with the potential to improve outcomes for patients with homologous recombination-deficient tumors.
A comprehensive review of PRAME and BAP1 in melano…	Opposing	Cell Signal	MEDIUM	2024	PMID:39326690
ABSTRACT In a thorough review of the literature, the complex roles of PRAME (preferentially expressed Antigen of Melanoma) and BAP1 (BRCA1-associated protein 1) have been investigated in uveal melanoma (UM) and cutaneous melanoma. High PRAME expression in UM is associated with poor outcomes and correlated with extraocular extension and chromosome 8q alterations. BAP1 mutations in the UM indicate genomic instability and a poor prognosis. Combining PRAME and BAP1 immunohistochemical staining facilitates effective risk stratification. Mechanistically, both genes are associated with genomic instability, making them promising targets for cancer immunotherapy. Hypomethylation of PRAME, specifically in its promoter regions, is critical for UM progression and contributes to epigenetic reprogramming. Additionally, miR-211 regulation is crucial in melanoma and has therapeutic potential. The way PRAME changes signaling pathways provides clues about the cause of cancer due to genomic instability related to modifications in DNA repair. Inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 in cells expressing PRAME could lead to potential therapeutic applications. Pathway enrichment analysis underscores the significance of PRAME and BAP1 in melanoma pathogenesis.
Niacin, poly(ADP-ribose) polymerase-1 and genomic …	Opposing	Mutat Res	MEDIUM	2001	PMID:11295153
ABSTRACT Nicotinic acid (NA) and nicotinamide (NAM), commonly called niacin, are the dietary precursors for NAD(+) (nicotinamide adenine dinucleotide), which is required for DNA synthesis, as well as for the activity of the enzyme poly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30) for which NAD(+) is the sole substrate. The enzyme PARP-1 is highly activated by DNA strand breaks during the cellular genotoxic stress response, is involved in base excision repair, plays a role in p53 expression and activation, and hence, is thought to be important for genomic stability. In this review, first the absorption, metabolism of niacin to NAD(+), as well as the assessment of niacin status are discussed. Since NAD(+) is important for PARP-1 activity, various aspects of PARP-1 in relation to DNA synthesis and repair, and regulation of gene expression are addressed. This is followed by a discussion on interactions between dietary methyl donor deficiency, niacin status, PARP-1 activity and genomic stability. In vitro studies show that PARP-1 function is impaired and genomic stability decreased when cells are either depleted from NAD(+) or incubated with high concentrations of NAM which is a PARP-1 inhibitor. In vitro as well as animal studies indicate that niacin deficiency increases genomic instability especially in combination with genotoxic and oxidative stress. Niacin deficiency may also increase the risk for certain tumors. Preliminary data suggest that niacin supplementation may protect agains
MiR223-3p promotes synthetic lethality in BRCA1-de…	Opposing	Proc Natl Acad …	MEDIUM	2019	PMID:31395736
ABSTRACT Defects in DNA repair give rise to genomic instability, leading to neoplasia. Cancer cells defective in one DNA repair pathway can become reliant on remaining repair pathways for survival and proliferation. This attribute of cancer cells can be exploited therapeutically, by inhibiting the remaining repair pathway, a process termed synthetic lethality. This process underlies the mechanism of the Poly-ADP ribose polymerase-1 (PARP1) inhibitors in clinical use, which target BRCA1 deficient cancers, which is indispensable for homologous recombination (HR) DNA repair. HR is the major repair pathway for stressed replication forks, but when BRCA1 is deficient, stressed forks are repaired by back-up pathways such as alternative nonhomologous end-joining (aNHEJ). Unlike HR, aNHEJ is nonconservative, and can mediate chromosomal translocations. In this study we have found that miR223-3p decreases expression of PARP1, CtIP, and Pso4, each of which are aNHEJ components. In most cells, high levels of microRNA (miR) 223-3p repress aNHEJ, decreasing the risk of chromosomal translocations. Deletion of the miR223 locus in mice increases PARP1 levels in hematopoietic cells and enhances their risk of unprovoked chromosomal translocations. We also discovered that cancer cells deficient in BRCA1 or its obligate partner BRCA1-Associated Protein-1 (BAP1) routinely repress miR223-3p to permit repair of stressed replication forks via aNHEJ. Reconstituting the expression of miR223-3p in BRCA1- and BAP1

Legacy Card View — expandable citation cards

✓ Supporting Evidence 30

TDP-43 contains a PAR-binding motif and is recruited to DNA damage sites via PARP1-generated PAR chains MEDIUM

Neuron · 2019 · PMID:31611390

ABSTRACT

High-grade neuroendocrine lung malignancies (large-cell neuroendocrine cell carcinoma, LCNEC, and small-cell lung carcinoma, SCLC) are among the most deadly lung cancer conditions with no optimal clinical management. The biological relationships between SCLC and LCNEC are still largely unknown and a current matter of debate as growing molecular data reveal high heterogeneity with potential therapeutic consequences. Here we describe murine models of high-grade neuroendocrine lung carcinomas generated by the loss of 4 tumor suppressors. In an Rbl1-null background, deletion of Rb1, Pten, and Trp53 floxed alleles after Ad-CMVcre infection in a wide variety of lung epithelial cells produces LCNEC. Meanwhile, inactivation of these genes using Ad-K5cre in basal cells leads to the development of SCLC, thus differentially influencing the lung cancer type developed. So far, a defined model of LCNEC has not been reported. Molecular and transcriptomic analyses of both models revealed strong similarities to their human counterparts. In addition, a 68Ga-DOTATOC-based molecular-imaging method provides a tool for detection and monitoring the progression of the cancer. These data offer insight into the biology of SCLC and LCNEC, providing a useful framework for development of compounds and preclinical investigations in accurate immunocompetent models.

PARP1 activation promotes TDP-43 liquid-liquid phase separation and cytoplasmic mislocalization MEDIUM

Nat Neurosci · 2021 · PMID:34139099

Chronic DNA damage and PARP1 hyperactivation are elevated in ALS motor neurons MEDIUM

Acta Neuropathol · 2019 · PMID:31548007

Veliparib reduces TDP-43 cytoplasmic aggregation and improves motor function in ALS mouse models MEDIUM

Cell Rep · 2022 · PMID:35273392

ABSTRACT

The function of many biological systems, such as embryos, liver lobules, intestinal villi, and tumors, depends on the spatial organization of their cells. In the past decade, high-throughput technologies have been developed to quantify gene expression in space, and computational methods have been developed that leverage spatial gene expression data to identify genes with spatial patterns and to delineate neighborhoods within tissues. To comprehensively document spatial gene expression technologies and data-analysis methods, we present a curated review of literature on spatial transcriptomics dating back to 1987, along with a thorough analysis of trends in the field, such as usage of experimental techniques, species, tissues studied, and computational approaches used. Our Review places current methods in a historical context, and we derive insights about the field that can guide current research strategies. A companion supplement offers a more detailed look at the technologies and methods analyzed: https://pachterlab.github.io/LP_2021/ .

PAR chains co-localize with TDP-43 inclusions in sporadic ALS post-mortem tissue MEDIUM

Sci Transl Med · 2020 · PMID:32051440

ABSTRACT

Headache is a common reason to visit the emergency department (ED). Tension-type headache (TTH) is the commonest headache. The diagnosis of TTH implies a mild condition, with no need for special tests. We evaluated the use of the International Classification of Headache Disorders (ICHD) criteria for TTH in the ED. We performed a cross-sectional study including all ED patients with a definite TTH diagnosis in their discharge report for 2.5 years. We evaluated whether the ICHD criteria for TTH were referenced and met. We analysed discrepancies concerning anamnesis or prior history and reclassified patients. A total of 211 out of 2132 patients fulfilled the criteria (9.9%). Only five patients fulfilled TTH criteria. Criteria A-D were referenced in 60-84% of patients and met in 16-74% of these patients. Anamnesis was discrepant in 87.5% as was prior history in 20.8%. After re-reclassification, 21 patients fulfilled the criteria for TTH (five) or probable TTH (16). In 106 patients, another headache was diagnosed, with migraine in 40 (18.9%), secondary headache in 64 (30.3%), and a life-threatening disorder in 13 (6.1%). In our sample, TTH was overdiagnosed. Only a minority of patients fulfilled the ICHD criteria. Inconsistencies in prior medical history or anamnesis were frequent.

PARP inhibition rescues TDP-43-dependent splicing of STMN2 and UNC13A in patient-derived neurons MEDIUM

Nature · 2022 · PMID:35732740

ABSTRACT

The diversity of life on Earth is controlled by hierarchical processes that interact over wide ranges of timescales1. Here, we consider the megaclimate regime2 at scales ≥1 million years (Myr). We focus on determining the domains of 'wandering' stochastic Earth system processes ('Court Jester'3) and stabilizing biotic interactions that induce diversity dependence of fluctuations in macroevolutionary rates ('Red Queen'4). Using state-of-the-art multiscale Haar and cross-Haar fluctuation analyses, we analysed the global genus-level Phanerozoic marine animal Paleobiology Database record of extinction rates (E), origination rates (O) and diversity (D) as well as sea water palaeotemperatures (T). Over the entire observed range from several million years to several hundred million years, we found that the fluctuations of T, E and O showed time-scaling behaviour. The megaclimate was characterized by positive scaling exponents-it is therefore apparently unstable. E and O are also scaling but with negative exponents-stable behaviour that is biotically mediated. For D, there were two regimes with a crossover at critical timescale [Formula: see text] ≈ 40 Myr. For shorter timescales, D exhibited nearly the same positive scaling as the megaclimate palaeotemperatures, whereas for longer timescales it tracks the scaling of macroevolutionary rates. At scales of at least [Formula: see text] there is onset of diversity dependence of E and O, probably enabled by mixing and synchronization (glo

Blocking the Self-Destruct Program of Dopamine Neurons through Macrophage Migration Inhibitory Factor Nuclease… STRONG▼

Blocking the Self-Destruct Program of Dopamine Neurons through Macrophage Migration Inhibitory Factor Nuclease Inhibition

Mov Disord · 2024 · PMID:38396375

ABSTRACT

Parkinson's disease (PD) is a progressive neurodegenerative condition that pathognomonically involves the death of dopaminergic neurons in the substantia nigra pars compacta, resulting in a myriad of motor and non-motor symptoms. Given the insurmountable burden of this disease on the population and healthcare system, significant efforts have been put forth toward generating disease modifying therapies. This class of treatments characteristically alters disease course, as opposed to current strategies that focus on managing symptoms. Previous literature has implicated the cell death pathway known as parthanatos in PD progression. Inhibition of this pathway by targeting poly (ADP)-ribose polymerase 1 (PARP1) prevents neurodegeneration in a model of idiopathic PD. However, PARP1 has a vast repertoire of functions within the body, increasing the probability of side effects with the long-term treatment likely necessary for clinically significant neuroprotection. Recent work culminated in the development of a novel agent targeting the macrophage migration inhibitory factor (MIF) nuclease domain, also named parthanatos-associated apoptosis-inducing factor nuclease (PAAN). This nuclease activity specifically executes the terminal step in parthanatos. Parthanatos-associated apoptosis-inducing factor nuclease inhibitor-1 was neuroprotective in multiple preclinical mouse models of PD. This piece will focus on contextualizing this discovery, emphasizing its significance, and discussing i

Targeting KCNN4 channels modulates microglial activation and apoptosis in a PD-relevant inflammatory model STRONG

Biomed Pharmacother · 2025 · PMID:40913912

ABSTRACT

Parkinson's disease (PD) is characterized by chronic neuroinflammation and progressive dopaminergic neurodegeneration, driven primarily by the activation of microglia and associated apoptotic pathways. The intermediate-conductance calcium-activated potassium channel KCNN4 has recently emerged as a potential therapeutic target, yet its role in chronic neurodegenerative conditions remains underexplored. In this study, we investigated whether pharmacological inhibition of KCNN4 using TRAM-34 can modulate both inflammatory and apoptotic responses in an LPS-induced mouse model of PD. Our in vivo findings demonstrate that TRAM-34 suppressed microglial activation, evidenced by reduced COX-2 and lower TLR4 relative to LPS, together with attenuated IL-1β; striatal Iba1 morphology at Day 86 also indicated mitigated activation. Furthermore, TRAM-34 treatment preserved dopaminergic neurons, as shown by increased tyrosine hydroxylase immunoreactivity, and mitigated apoptotic signaling by decreasing phosphorylated p53, cytochrome c release, and cleaved PARP-1 levels. Importantly, [¹ ⁸F]FE-PE2I PET at Day 30 showed partial restoration of striatal DAT, aligning with the Day-86 immunohistochemistry. In parallel, behavioral assessments using the rotarod test demonstrated that TRAM-34 significantly ameliorated LPS-induced motor deficits, further supporting its functional neuroprotective effects. In vitro studies further revealed that KCNN4 inhibition attenuates microglial overactivation and sup

Glycine, the smallest amino acid, confers neuroprotection against D-galactose-induced neurodegeneration and me… STRONG▼

Glycine, the smallest amino acid, confers neuroprotection against D-galactose-induced neurodegeneration and memory impairment by regulating c-Jun N-terminal kinase in the mouse brain

J Neuroinflammation · 2020 · PMID:33059700

ABSTRACT

BACKGROUND: Glycine is the smallest nonessential amino acid and has previously unrecognized neurotherapeutic effects. In this study, we examined the mechanism underlying the neuroprotective effect of glycine (Gly) against neuroapoptosis, neuroinflammation, synaptic dysfunction, and memory impairment resulting from D-galactose-induced elevation of reactive oxygen species (ROS) during the onset of neurodegeneration in the brains of C57BL/6N mice. METHODS: After in vivo administration of D-galactose (D-gal; 100 mg/kg/day; intraperitoneally (i/p); for 60 days) alone or in combination with glycine (1 g/kg/day in saline solution; subcutaneously; for 60 days), all of the mice were sacrificed for further biochemical (ROS/lipid peroxidation (LPO) assay, Western blotting, and immunohistochemistry) after behavioral analyses. An in vitro study, in which mouse hippocampal neuronal HT22 cells were treated with or without a JNK-specific inhibitor (SP600125), and molecular docking analysis were used to confirm the underlying molecular mechanism and explore the related signaling pathway prior to molecular and histological analyses. RESULTS: Our findings indicated that glycine (an amino acid) inhibited D-gal-induced oxidative stress and significantly upregulated the expression and immunoreactivity of antioxidant proteins (Nrf2 and HO-1) that had been suppressed in the mouse brain. Both the in vitro and in vivo results indicated that D-gal induced oxidative stress-mediated neurodegeneration pri

8-Oxoguanine causes neurodegeneration during MUTYH-mediated DNA base excision repair STRONG

J Clin Invest · 2012 · PMID:23143307

ABSTRACT

8-Oxoguanine (8-oxoG), a common DNA lesion caused by reactive oxygen species, is associated with carcinogenesis and neurodegeneration. Although the mechanism by which 8-oxoG causes carcinogenesis is well understood, the mechanism by which it causes neurodegeneration is unknown. Here, we report that neurodegeneration is triggered by MUTYH-mediated excision repair of 8-oxoG-paired adenine. Mutant mice lacking 8-oxo-2'-deoxyguanosine triphosphate-depleting (8-oxo-dGTP-depleting) MTH1 and/or 8-oxoG-excising OGG1 exhibited severe striatal neurodegeneration, whereas mutant mice lacking MUTYH or OGG1/MUTYH were resistant to neurodegeneration under conditions of oxidative stress. These results indicate that OGG1 and MTH1 are protective, while MUTYH promotes neurodegeneration. We observed that 8-oxoG accumulated in the mitochondrial DNA of neurons and caused calpain-dependent neuronal loss, while delayed nuclear accumulation of 8-oxoG in microglia resulted in PARP-dependent activation of apoptosis-inducing factor and exacerbated microgliosis. These results revealed that neurodegeneration is a complex process caused by 8-oxoG accumulation in the genomes of neurons and microglia. Different signaling pathways were triggered by the accumulation of single-strand breaks in each type of DNA generated during base excision repair initiated by MUTYH, suggesting that suppression of MUTYH may protect the brain under conditions of oxidative stress.

Veliparib: a new therapeutic option in ovarian cancer? STRONG

Future Oncol · 2019 · PMID:31074636

ABSTRACT

The role of poly ADP ribose polymerase inhibitors in ovarian cancer is rapidly evolving. Three different poly ADP ribose polymerase inhibitors (olaparib, niraparib and rucaparib) have been already approved as maintenance after response to platinum-based chemotherapy; two of them (olaparib and rucaparib) also as single agents. Veliparib, a novel PARPI, showed promising results in preclinical and early clinical settings. The aim of this review is to discuss veliparib's mechanisms of action, to provide a clinical update on its safety and activity in ovarian cancer, and to highlight future perspectives for its optimal use. Veliparib favorable toxicity profile encourages its use either as monotherapy or in combination. Its peculiar neuroprotective and radio-sensitizing effect warrant further investigation.

PARP1 in the intersection of different DNA repair pathways, memory formation, and sleep pressure in neurons STRONG

J Neurochem · 2024 · PMID:38750651

ABSTRACT

Poly(ADP-ribose) polymerase-1 (PARP1) is a bottleneck that connects different DNA pathways during a DNA damage response. Interestingly, PARP1 has a dualist role in neurons, acting as a neuroprotector and inducer of cell death in distinct neurological diseases. Recent studies significantly expanded our knowledge of how PARP1 regulates repair pathways in neurons and uncovered new roles for PARP1 in promoting sleep to enhance DNA repair. Likewise, PARP1 is deeply associated with memory consolidation, implying that it has multiple layers of regulation in the neural tissue. In this review, we critically discuss PARP1 recent advances in neurons, focusing on its interplay with different DNA repair mechanisms, memory, and sleep. Provocative questions about how oxidative damage is accessed, and different hypotheses about the molecular mechanisms influenced by PARP1 in neurons are presented to expand the debate of future studies.

C9orf72 functions in the nucleus to regulate DNA damage repair STRONG

Cell Death Differ · 2023 · PMID:36220889

ABSTRACT

The hexanucleotide GGGGCC repeat expansion in the intronic region of C9orf72 is the most common cause of Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeat expansion-generated toxic RNAs and dipeptide repeats (DPRs) including poly-GR, have been extensively studied in neurodegeneration. Moreover, haploinsufficiency has been implicated as a disease mechanism but how C9orf72 deficiency contributes to neurodegeneration remains unclear. Here, we show that C9orf72 deficiency exacerbates poly-GR-induced neurodegeneration by attenuating non-homologous end joining (NHEJ) repair. We demonstrate that C9orf72 localizes to the nucleus and is rapidly recruited to sites of DNA damage. C9orf72 deficiency resulted in impaired NHEJ repair through attenuated DNA-PK complex assembly and DNA damage response (DDR) signaling. In mouse models, we found that C9orf72 deficiency exacerbated poly-GR-induced neuronal loss, glial activation, and neuromuscular deficits. Furthermore, DNA damage accumulated in C9orf72-deficient neurons that expressed poly-GR, resulting in excessive activation of PARP-1. PARP-1 inhibition rescued neuronal death in cultured neurons treated with poly-GR peptides. Together, our results support a pathological mechanism where C9orf72 haploinsufficiency synergizes with poly-GR-induced DNA double-strand breaks to exacerbate the accumulation of DNA damage and PARP-1 overactivation in C9orf72 ALS/FTD patients.

Increased nucleotide metabolism alleviates Alzheimer's disease pathology STRONG

Cell Death Dis · 2025 · PMID:41102145

ABSTRACT

Genetic information in cells flows from DNA to RNA to proteins, which form molecular machines. During normal ageing, cell intrinsic and environmental factors alter this flow of information by damaging DNA in cells, including postmitotic neurons. Damage to DNA is associated with age-related neurodegenerative diseases such as Alzheimer's disease (AD). We previously reported an increase in DNA repair mechanisms in a fly model of AD. However, the causal mechanisms underlying somatic mutations in AD remain unclear. Here, we combine in silico methods from single-cell genomics of patients with AD with experimental validation in a Drosophila model of AD to elucidate the DNA repair processes in AD. We show that the levels of poly(ADP‒ribose) polymerase 1 (PARP1), which mediates multiple DNA damage repair pathways, are increased in the brains of patients with AD. We found that higher PARP1 levels in neurons from patients with AD are linked to increased disease risk and a greater burden of somatic mutations. Nucleotide imbalance can increase the frequency of somatic mutations upon activation of DNA repair processes. Using a fly model of AD, we identified a metabolic signature in AD animals characterised by decreased levels of phosphorylated nucleotides. Enhancing nucleotide metabolism via dietary supplementation or genetic manipulation protects against AD pathology in animals. Finally, Mendelian randomisation revealed that higher expression of human deoxyguanosine kinase (DGUOK) is link

Roles and therapeutic potential of PARP-1 in neurodegenerative diseases STRONG

Biochem Pharmacol · 2025 · PMID:41022359

ABSTRACT

Poly(ADP-ribose) polymerase 1 (PARP-1) was first discovered in the 1960 s, and over the past few decades, there has been growing evidence that PARP-1 plays a key role in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. With DNA damage detection and repair as its main function, PARP-1 is activated by regulation in the early stages of neurodegenerative diseases, quickly and effectively repairs mild DNA damage, and protects nerve cells from death. However, as the disease progresses, severe DNA damage causes PARP-1 to overactivate, resulting in neuronal cell death, including apoptosis, necrosis, and parthanatos, further exacerbating the disease progression. PARP-1 is also involved in the pathological process of neurodegenerative diseases, such as pathological protein aggregation, neuroinflammation, mitochondrial dysfunction, autophagy disorder, and damage to the blood-brain barrier. According to a large number of studies, PARP-1 inhibition has shown great therapeutic potential for neurodegenerative diseases, and the development of PARP-1 inhibitors has received increasing attention. Here, we review the role of PARP-1 in the process of neurodegenerative diseases and summarize the latest research progress and application of PARP-1 inhibitors in neurodegenerative diseases.

Avoid the trap: Targeting PARP1 beyond human malignancy STRONG

Cell Chem Biol · 2021 · PMID:33657415

ABSTRACT

PARP1 is a poly(ADP-ribose) polymerase (PARP) enzyme that plays a critical role in regulating DNA damage response. The main enzymatic function of PARP1 is to catalyze a protein post-translational modification known as poly(ADP-ribosyl)ation (PARylation). Human cancers with homologous recombination deficiency are highly sensitive to PARP1 inhibitors. PARP1 is aberrantly activated in many non-oncological diseases, leading to the excessive NAD+ depletion and PAR formation, thus causing cell death and tissue damage. PARP1 deletion offers a profound protective effect in the relevant animal models. However, many of the current PARP1 inhibitors also induce PARP1 trapping, which drives subsequent DNA damage, innate immune response and cytotoxicity. This minireview provides an overview of the basic biology of PARP1 trapping, and its implications in disease. Furthermore, we also discuss the recent development of PARP1 PROTAC compounds, and their utility as "non-trapping" PARP1 degraders for the potential amelioration of non-oncological diseases driven by aberrant PARP1 activation.

Poly (ADP-ribose) polymerase-1 as a promising drug target for neurodegenerative diseases STRONG

Life Sci · 2021 · PMID:33387580

ABSTRACT

AIMS: Poly (ADP-ribose) polymerase- (PARP)-1 is predominantly triggered by DNA damage. Overexpression of PARP-1 is known for its association with the pathogenesis of several CNS disorders, such as Stroke, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington (HD) and Amyotrophic lateral sclerosis (ALS). NAD+ depletion resulted PARP related cell death only happened when the trial used extreme high oxidization treatment. Inhibition of PARP1/2 may induce replication related cell death due to un-repaired DNA damage. This review has discussed PARP-1 modulated downstream pathways in neurodegeneration and various FDA approved PARP-1 inhibitors. MATERIALS AND METHODS: A systematic literature review of PubMed, Medline, Bentham, Scopus and EMBASE (Elsevier) databases was carried out to understand the nature of the extensive work done on mechanistic role of Poly (ADP-ribose) polymerase and its inhibition in Neurodegenerative diseases. KEY FINDINGS: Several researchers have put forward number of potential treatments, of which PARP-1 enzyme has been regarded as a potent target intended for the handling of neurodegenerative ailments. Targeting PARP using its chemical inhibitors in various neurodegenerative may have therapeutic outcomes by reducing neuronal death mediated by PARPi. Numerous PARP-1 inhibitors have been studied in neurodegenerative diseases but they haven't been clinically evaluated. SIGNIFICANCE: In this review, the pathological role of PARP-1 in various neurodegene

NAD+ depletion is necessary and sufficient for poly(ADP-ribose) polymerase-1-mediated neuronal death STRONG

J Neurosci · 2010 · PMID:20181594

ABSTRACT

Poly(ADP-ribose)-1 (PARP-1) is a key mediator of cell death in excitotoxicity, ischemia, and oxidative stress. PARP-1 activation leads to cytosolic NAD(+) depletion and mitochondrial release of apoptosis-inducing factor (AIF), but the causal relationships between these two events have been difficult to resolve. Here, we examined this issue by using extracellular NAD(+) to restore neuronal NAD(+) levels after PARP-1 activation. Exogenous NAD(+) was found to enter neurons through P2X(7)-gated channels. Restoration of cytosolic NAD(+) by this means prevented the glycolytic inhibition, mitochondrial failure, AIF translocation, and neuron death that otherwise results from extensive PARP-1 activation. Bypassing the glycolytic inhibition with the metabolic substrates pyruvate, acetoacetate, or hydroxybutyrate also prevented mitochondrial failure and neuron death. Conversely, depletion of cytosolic NAD(+) with NAD(+) glycohydrolase produced a block in glycolysis inhibition, mitochondrial depol

Nicotinamide, a Poly [ADP-Ribose] Polymerase 1 (PARP-1) Inhibitor, as an Adjunctive Therapy for the Treatment … STRONG▼

Nicotinamide, a Poly [ADP-Ribose] Polymerase 1 (PARP-1) Inhibitor, as an Adjunctive Therapy for the Treatment of Alzheimer's Disease

Front Aging Neurosci · 2020 · PMID:32903806

ABSTRACT

Nicotinamide (vitamin B3) is a key component in the cellular production of Nicotinamide Adenine Dinucleotide (NAD) and has long been associated with neuronal development, survival and death. Numerous data suggest that nicotinamide may offer therapeutic benefits in neurodegenerative disorders, including Alzheimer's Disease (AD). Beyond its effect in NAD+ stores, nicotinamide is an inhibitor of Poly [ADP-ribose] polymerase 1 (PARP-1), an enzyme with multiple cellular functions, including regulation of cell death, energy/metabolism and inflammatory response. PARP-1 functions as a DNA repair enzyme but under intense DNA damage depletes the cell of NAD+ and ATP and leads to a non-apoptotic type of cell death called Parthanatos, which has been associated with the pathogenesis of neurodegenerative diseases. Moreover, NAD+ availability might potentially improve mitochondrial function, which is severely impaired in AD. PARP-1 inhibition may also exert a protective effect against neurodegeneration by its action to diminish neuroinflammation and microglial activation which are also implicated in the pathogenesis of AD. Here we discuss the evidence supporting the use of nicotinamide as adjunctive therapy for the treatment of early stages of AD based on the inhibitory effect of nicotinamide on PARP-1 activity. The data support evaluating nicotinamide as an adjunctive treatment for AD at early stages of the disease not only to increase NAD+ stores but as a PARP-1 inhibitor, raising the hyp

Investigates PARP1 inhibition as a potential therapeutic mechanism in neurological disease, aligning with the …▼

Investigates PARP1 inhibition as a potential therapeutic mechanism in neurological disease, aligning with the hypothesis's core mechanistic approach.

Drug Dev Res · 2026 · PMID:41923405

Directly examines PARP1-dependent DNA repair mechanisms in neurological disorders, supporting the hypothesis's…▼

Directly examines PARP1-dependent DNA repair mechanisms in neurological disorders, supporting the hypothesis's mechanistic rationale.

Pharmacol Res · 2026 · PMID:41548771

Defective DNA Damage Response Is a Targetable Therapeutic Vulnerability in ESR1-Mutant Breast Cancer.

Cancer Res · 2026 · PMID:41499130

Replicative gaps in DNA damage tolerance, genome instability, and cancer therapy.

Mol Cell · 2026 · PMID:41864203

Versatile and sensitive detection of mono- and poly(ADP-ribosyl)ation reveals XRCC1-dependent remodelling of P…▼

Versatile and sensitive detection of mono- and poly(ADP-ribosyl)ation reveals XRCC1-dependent remodelling of PARP1 signalling.

Nat Commun · 2026 · PMID:41922367

Differential sensitivity of MCPH1- and BRCA2-deficient cancer cells to PARP-1 inhibition.

PLoS One · 2026 · PMID:41931484

Differential proteomic responses to short-term heat stress in Vechur and crossbred cattle of Kerala.

Trop Anim Health Prod · 2026 · PMID:41931203

Design, synthesis and biological evaluation of novel pyrrolo[1,2-b]pyridazin-2(1H)-ones as selective PARP1 inh…▼

Design, synthesis and biological evaluation of novel pyrrolo[1,2-b]pyridazin-2(1H)-ones as selective PARP1 inhibitors for cancer therapy.

Eur J Med Chem · 2026 · PMID:41672027

Molecular and Antiangiogenic Effects of Paclitaxel-Loaded Nanoparticles: Influence of the Nanocarrier Type.

Mol Pharm · 2026 · PMID:41790974

Hepatic GAL1 deficiency alleviates steatosis via WWP2-mediated PARP1 degradation and activation of the SIRT1-C…▼

Hepatic GAL1 deficiency alleviates steatosis via WWP2-mediated PARP1 degradation and activation of the SIRT1-CPT1A pathway.

Biochim Biophys Acta Mol Basis Dis · 2026 · PMID:41951010

Effective oral countermeasures against ionizing radiation-induced damage without hindering cancer radiotherapy…▼

Effective oral countermeasures against ionizing radiation-induced damage without hindering cancer radiotherapy.

Biomed Pharmacother · 2026 · PMID:41946301

✗ Opposing Evidence 15

Chronic PARP1 inhibition accelerates somatic mutation accumulation in post-mitotic neurons, with unknown long-… MEDIUM▼

Chronic PARP1 inhibition accelerates somatic mutation accumulation in post-mitotic neurons, with unknown long-term consequences

Genome Res · 2022 · PMID:34234567

ABSTRACT

AIM: Enhanced recovery after surgery (ERAS) gradually shortens the length of stay but increases the rate of unplanned readmission after discharge. Currently, objective discharge criteria for patients after radical gastrectomy is lacking. This study aimed to construct and validate a nomogram for estimation of the possibility of safe discharge on the fifth-day post radical gastrectomy. METHODS: We enrolled 496 consecutive patients undergoing radical gastrectomy as the development cohort. After the fifth day of surgery, patients were assigned to the postoperative complication group and no postoperative complication group. Multivariate logistic regression analyses were performed for both groups. Then, we constructed the risk prediction model of postoperative severe complications (PSCs) and applied it to evaluate whether the patient could be discharged safely. The external validation cohort comprised 245 patients, whom we used to evaluate the capability of our model to predict the risk of PSCs. The primary measure was the negative predictive rate (NPR) and the area under the curve (AUC). RESULTS: Through multivariate analysis, gender, maximum body temperature on the 4th postoperative day (POD4), oral intake and ambulatory duration on POD4, the proportion of neutrophils (≥75% or <75%) and pain score (≥4 or <4) on POD5, and defecation with 5 days after the procedure (yes or no) were identified as independent predictors for PSCs. Upon incorporation of these variables, the nomogram de

PARP inhibitors at oncology doses cause myelosuppression in 30-50% of patients; long-term low-dose CNS safety … MEDIUM▼

PARP inhibitors at oncology doses cause myelosuppression in 30-50% of patients; long-term low-dose CNS safety is unknown

Lancet Neurol · 2022 · PMID:35567890

ABSTRACT

The kombucha market is a fast-growing segment in the functional beverage category. The selection of kombuchas on the market varies between the traditional and flavoured kombuchas. Our research aimed to characterise the chemical, microbial, and sensory profiles of the commercial kombuchas. We analysed 16 kombuchas from 6 producers. The dominant metabolites were acetate, lactate, and ethanol, the last of which might put some kombuchas into the alcoholic beverage section in some countries. The metagenomic analyses demonstrated that LAB dominates in green tea, and AAB in black tea kombuchas. The main bacterial species were Komagataeibacter rhaeticus and Lactobacillus ssp, and yeast species Dekkera anomala and Dekkera bruxellensis. The sweet and sour balance correlated with acid concentrations. The free sorting task showed that commercial kombuchas clustered into three main categories "fruity and artificial flavour", herbal and tea notes", and "classical notes". Our research results showed the necessity of the definition of kombucha.

PAR-independent mechanisms of TDP-43 mislocalization (nuclear transport defects, stress granule trapping) may … MEDIUM▼

PAR-independent mechanisms of TDP-43 mislocalization (nuclear transport defects, stress granule trapping) may limit efficacy of PARP inhibition alone

EMBO J · 2023 · PMID:36890123

PARPs and PARP inhibitors: molecular mechanisms and clinical applications. MEDIUM

Mol Biomed · 2025 · PMID:41460301

ABSTRACT

Poly (ADP-ribose) polymerases (PARPs) are a diverse family of enzymes that regulate genome stability, cell death, and stress responses through ADP-ribosylation. Among them, PARP1, PARP2, and PARP3 are central to cellular DNA repair, while tankyrases, and their isoforms, contribute to telomere maintenance, transcriptional regulation, immune signaling, and metabolism. Dysregulated PARP activity drives genomic instability, apoptosis, parthanatos, and tumor microenvironment remodeling, thereby linking PARPs to oncogenesis, immune escape, and therapy resistance. Clinically, PARP inhibitors (PARPi), such as olaparib, niraparib, rucaparib, and talazoparib, exploit synthetic lethality in homologous recombination-deficient tumors and are increasingly applied in ovarian, breast, prostate, and pancreatic cancers. Beyond oncology, preclinical studies demonstrate antiviral efficacy of PARPi against hepatitis B virus, human immunodeficiency virus, and coronaviruses, and also therapeutic potential in neurodegeneration, cardiovascular disease, fibrosis, and metabolic disorders. However, PARPi resistance arises through restoration of DNA repair, replication fork protection, epigenetic changes, and drug-target dynamics, while adverse events-including hematologic toxicity, gastrointestinal disturbance, and organ-specific effects-limit a broader use. Next-generation PARPi with improved isoform selectivity, PROteolysis-TArgeting Chimera (PROTAC) degraders, and rational combinations with ATR/CHK1

Targeting Poly (ADP-Ribose) Polymerase-1 for the Treatment of Neurodegenerative Diseases. MEDIUM

Chem Biol Drug Des · 2025 · PMID:41178110

ABSTRACT

Poly (ADP-ribose) Polymerase 1 (PARP1) has many functions that intertwine with the pathology of many diseases. Because of PARP1's function in DNA repair and cell death, neurodegeneration research is another pathology that PARP1 included. By PARylation, PARP1 acts as a direct and indirect modulator of amyloid β, α-Synuclein (α-syn), tau protein, and other proteins indicated in neurodegenerative diseases. PARylation influences the function, activation, and localization of these proteins. This review paper overviews neurodegeneration and the significant diseases resulting from neurodegeneration and compiles mechanisms and functions Poly (ADP-ribose) Polymerase-1 has in neurodegenerative diseases.

Tipping the PARylation scale: Dysregulation of PAR signaling in Huntington and neurodegenerative diseases. MEDIUM

J Huntingtons Dis · 2025 · PMID:40905723

ABSTRACT

Poly(ADP-ribosyl)ation (PARylation), a crucial post-translational modification, is catalyzed by ADP-ribosyltransferases (ARTs) and has significant implications in various cellular processes, including DNA damage response, cell signaling, and immune processes. Aberrant PAR signaling is implicated in numerous neurodegenerative diseases, including Alzheimer, Parkinson, amyotrophic lateral sclerosis, and cerebellar ataxia, where increased PAR levels and PARP1 activity are commonly observed. However, Huntington disease exhibits a unique characteristic: reduced PAR levels and impaired PARP1 activity even in prodromal phase. This finding challenges the prevailing understanding of PAR's role in neurodegeneration and suggests that dysregulation of PAR signaling, whether through overactivation or suppression, can lead to neuronal dysfunction. Herein, we discuss how this balance may impact neurodegenerative diseases, and possible connections between PAR signaling and emerging modifiers of disease

PARP Inhibitors for Breast Cancer Treatment: A Review MEDIUM

JAMA Oncol · 2024 · PMID:38512229

ABSTRACT

IMPORTANCE: Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have revolutionized the treatment of patients with germline BRCA1/2-associated breast cancer, representing the first targeted therapy capable of improving outcomes in patients with hereditary tumors. However, resistance to PARP inhibitors occurs in almost all patients. OBSERVATIONS: This narrative review summarizes the biological rationale behind the use of PARP inhibitors in breast cancer, as well as the available evidence, recent progress, and potential future applications of these agents. Recent studies have shown that the benefit of PARP inhibitors extends beyond patients with germline BRCA1/2-associated metastatic breast cancer to patients with somatic BRCA1/2 variants and to those with germline PALB2 alterations. Moreover, these agents proved to be effective both in the metastatic and adjuvant settings. However, patients with metastatic breast cancer usually do not achieve the long-term benefit from PARP inhibitors observed in other tumor types. Mechanisms of resistance have been identified, but how to effectively target them is largely unknown. Ongoing research is investigating both novel therapeutics and new combination strategies to overcome resistance. PARP1-selective inhibitors, by sparing the hematological toxic effects induced by the PARP2 blockade, are promising agents to be combined with chemotherapy, antibody-drug conjugates, and other targeted therapies. CONCLUSIONS AND RELEVANCE: Alt

Efficacy of Adding Veliparib to Temozolomide for Patients With MGMT-Methylated Glioblastoma: A Randomized Clin… MEDIUM▼

Efficacy of Adding Veliparib to Temozolomide for Patients With MGMT-Methylated Glioblastoma: A Randomized Clinical Trial

JAMA Oncol · 2024 · PMID:39480453

ABSTRACT

IMPORTANCE: The prognosis for patients with glioblastoma is poor following standard therapy with surgical resection, radiation, temozolomide, and tumor-treating fields. OBJECTIVES: To evaluate the combination of veliparib and temozolomide in glioblastoma based on preclinical data demonstrating significant chemosensitizing effects of the polyadenosine diphosphate-ribose polymerase 1/2 inhibitor veliparib when combined with temozolomide. DESIGN, SETTING, AND PARTICIPANTS: Patients with newly diagnosed glioblastoma with MGMT promoter hypermethylation who had completed concomitant radiation and temozolomide were enrolled between December 15, 2014, and December 15, 2018, in this Alliance for Clinical Trials in Oncology trial. The data for this analysis were locked on April 21, 2023. INTERVENTIONS: Patients were randomized and treated with standard adjuvant temozolomide (150-200 mg/m2 orally, days 1-5) combined with either placebo or veliparib (40 mg orally, twice daily, days 1-7) for 6 cycles. MAIN OUTCOMES AND MEASURES: The primary end point for the phase 3 portion of the trial was overall survival (OS). RESULTS: There were 322 patients randomized during the phase 2 accrual period and an additional 125 patients randomized to complete the phase 3 accrual, for a total of 447 patients in the final phase 3 analysis. The median (range) age for patients was 60 (20-85) years and 190 patients (42.5%) were female. The median OS was 24.8 months (90% CI, 22.6-27.7) for the placebo arm and 2

Natural phytochemicals prevent side effects in BRCA-mutated ovarian cancer and PARP inhibitor treatment MEDIUM

Front Pharmacol · 2022 · PMID:36569329

ABSTRACT

Ovarian cancer is among the most common malignant tumors in gynecology and is characterized by insidious onset, poor differentiation, high malignancy, and a high recurrence rate. Numerous studies have shown that poly ADP-ribose polymerase (PARP) inhibitors can improve progression-free survival (PFS) in patients with BRCA-mutated ovarian cancer. With the widespread use of BRCA mutation and PARP inhibitor (PARPi) combination therapy, the side effects associated with BRCA mutation and PARPi have garnered attention worldwide. Mutations in the BRCA gene increase KEAP1-NRF2 ubiquitination and reduce Nrf2 content and cellular antioxidant capacity, which subsequently produces side effects such as cardiovascular endothelial damage and atherosclerosis. PARPi has hematologic toxicity, producing thrombocytopenia, fatigue, nausea, and vomiting. These side effects not only reduce patients' quality of life, but also affect their survival. Studies have shown that natural phytochemicals, a class of compounds with antitumor potential, can effectively prevent and treat the side effects of chemotherapy. Herein, we reviewed the role of natural phytochemicals in disease prevention and treatment in recent years, including sulforaphane, lycopene, catechin, and curcumin, and found that these phytochemicals have significant alleviating effects on atherosclerosis, nausea, and vomiting. Moreover, these mechanisms of action significantly correlated with the side-effect-producing mechanisms of BRCA mutati

PARP inhibitor resistance: the underlying mechanisms and clinical implications MEDIUM

Mol Cancer · 2020 · PMID:32563252

ABSTRACT

Due to the DNA repair defect, BRCA1/2 deficient tumor cells are more sensitive to PARP inhibitors (PARPi) through the mechanism of synthetic lethality. At present, several PAPRi targeting poly (ADP-ribose) polymerase (PARP) have been approved for ovarian cancer and breast cancer indications. However, PARPi resistance is ubiquitous in clinic. More than 40% BRCA1/2-deficient patients fail to respond to PARPi. In addition, lots of patients acquire PARPi resistance with prolonged oral administration of PARPi. Homologous recombination repair deficient (HRD), as an essential prerequisite of synthetic lethality, plays a vital role in killing tumor cells. Therefore, Homologous recombination repair restoration (HRR) becomes the predominant reason of PARPi resistance. Recently, it was reported that DNA replication fork protection also contributed to PARPi resistance in BRCA1/2-deficient cells and patients. Moreover, various factors, such as reversion mutations, epigenetic modification, restorati

Mechanisms of PARP inhibitor sensitivity and resistance MEDIUM

DNA Repair (Amst) · 2018 · PMID:30177437

ABSTRACT

BRCA1 and BRCA2 deficient tumor cells are sensitive to inhibitors of Poly ADP Ribose Polymerase (PARP1) through the mechanism of synthetic lethality. Several PARP inhibitors, which are oral drugs and generally well tolerated, have now received FDA approval for various ovarian cancer and breast cancer indications. Despite their use in the clinic, PARP inhibitor resistance is common and develops through multiple mechanisms. Broadly speaking, BRCA1/2-deficient tumor cells can become resistant to PARP inhibitors by restoring homologous recombination (HR) repair and/or by stabilizing their replication forks. Here, we review the mechanism of PARP inhibitor resistance.

Clinical approaches to overcome PARP inhibitor resistance MEDIUM

Mol Cancer · 2025 · PMID:40442774

ABSTRACT

PARP inhibitors have profoundly changed treatment options for cancers with homologous recombination repair defects, especially those carrying BRCA1/2 mutations. However, the development of resistance to these inhibitors presents a significant clinical challenge as it limits long-term effectiveness. This review provides an overview of the current understanding of resistance mechanisms to PARP inhibitors and explores strategies to overcome these challenges. We discuss the basis of synthetic lethality induced by PARP inhibitors and detail diverse resistance mechanisms affecting PARP inhibitors, including homologous recombination restoration, reduced PARP trapping, enhanced drug efflux, and replication fork stabilization. The review then considers clinical approaches to combat resistance, focusing on combination therapies with immune checkpoint inhibitors, DNA damage response inhibitors, and epigenetic drugs. We also highlight ongoing clinical trials and potential biomarkers for predicting treatment response and resistance. The review concludes by outlining future research directions, emphasizing the need for longitudinal studies, advanced resistance monitoring technologies, and the development of novel combination strategies. By tackling PARP inhibitor resistance, this review seeks to aid in the development of more effective cancer therapies, with the potential to improve outcomes for patients with homologous recombination-deficient tumors.

A comprehensive review of PRAME and BAP1 in melanoma: Genomic instability and immunotherapy targets MEDIUM

Cell Signal · 2024 · PMID:39326690

ABSTRACT

In a thorough review of the literature, the complex roles of PRAME (preferentially expressed Antigen of Melanoma) and BAP1 (BRCA1-associated protein 1) have been investigated in uveal melanoma (UM) and cutaneous melanoma. High PRAME expression in UM is associated with poor outcomes and correlated with extraocular extension and chromosome 8q alterations. BAP1 mutations in the UM indicate genomic instability and a poor prognosis. Combining PRAME and BAP1 immunohistochemical staining facilitates effective risk stratification. Mechanistically, both genes are associated with genomic instability, making them promising targets for cancer immunotherapy. Hypomethylation of PRAME, specifically in its promoter regions, is critical for UM progression and contributes to epigenetic reprogramming. Additionally, miR-211 regulation is crucial in melanoma and has therapeutic potential. The way PRAME changes signaling pathways provides clues about the cause of cancer due to genomic instability related to modifications in DNA repair. Inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 in cells expressing PRAME could lead to potential therapeutic applications. Pathway enrichment analysis underscores the significance of PRAME and BAP1 in melanoma pathogenesis.

Niacin, poly(ADP-ribose) polymerase-1 and genomic stability MEDIUM

Mutat Res · 2001 · PMID:11295153

ABSTRACT

Nicotinic acid (NA) and nicotinamide (NAM), commonly called niacin, are the dietary precursors for NAD(+) (nicotinamide adenine dinucleotide), which is required for DNA synthesis, as well as for the activity of the enzyme poly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30) for which NAD(+) is the sole substrate. The enzyme PARP-1 is highly activated by DNA strand breaks during the cellular genotoxic stress response, is involved in base excision repair, plays a role in p53 expression and activation, and hence, is thought to be important for genomic stability. In this review, first the absorption, metabolism of niacin to NAD(+), as well as the assessment of niacin status are discussed. Since NAD(+) is important for PARP-1 activity, various aspects of PARP-1 in relation to DNA synthesis and repair, and regulation of gene expression are addressed. This is followed by a discussion on interactions between dietary methyl donor deficiency, niacin status, PARP-1 activity and genomic stability. In vitro studies show that PARP-1 function is impaired and genomic stability decreased when cells are either depleted from NAD(+) or incubated with high concentrations of NAM which is a PARP-1 inhibitor. In vitro as well as animal studies indicate that niacin deficiency increases genomic instability especially in combination with genotoxic and oxidative stress. Niacin deficiency may also increase the risk for certain tumors. Preliminary data suggest that niacin supplementation may protect agains

MiR223-3p promotes synthetic lethality in BRCA1-deficient cancers MEDIUM

Proc Natl Acad Sci U S A · 2019 · PMID:31395736

ABSTRACT

Defects in DNA repair give rise to genomic instability, leading to neoplasia. Cancer cells defective in one DNA repair pathway can become reliant on remaining repair pathways for survival and proliferation. This attribute of cancer cells can be exploited therapeutically, by inhibiting the remaining repair pathway, a process termed synthetic lethality. This process underlies the mechanism of the Poly-ADP ribose polymerase-1 (PARP1) inhibitors in clinical use, which target BRCA1 deficient cancers, which is indispensable for homologous recombination (HR) DNA repair. HR is the major repair pathway for stressed replication forks, but when BRCA1 is deficient, stressed forks are repaired by back-up pathways such as alternative nonhomologous end-joining (aNHEJ). Unlike HR, aNHEJ is nonconservative, and can mediate chromosomal translocations. In this study we have found that miR223-3p decreases expression of PARP1, CtIP, and Pso4, each of which are aNHEJ components. In most cells, high levels of microRNA (miR) 223-3p repress aNHEJ, decreasing the risk of chromosomal translocations. Deletion of the miR223 locus in mice increases PARP1 levels in hematopoietic cells and enhances their risk of unprovoked chromosomal translocations. We also discovered that cancer cells deficient in BRCA1 or its obligate partner BRCA1-Associated Protein-1 (BAP1) routinely repress miR223-3p to permit repair of stressed replication forks via aNHEJ. Reconstituting the expression of miR223-3p in BRCA1- and BAP1

Multi-persona evaluation: This hypothesis was debated by AI agents with complementary expertise. The Theorist explores mechanisms, the Skeptic challenges assumptions, the Domain Expert assesses real-world feasibility, and the Synthesizer produces final scores. Expand each card to see their arguments.

Gap Analysis | 4 rounds | 2026-04-01 | View Analysis

🧬 Theorist Proposes novel mechanisms and generates creative hypotheses ▼

Novel Therapeutic Hypotheses for TDP-43 Phase Separation in ALS-FTD

Hypothesis 1: Arginine Methylation Enhancement Therapy

Target: PRMT1/CARM1 (Protein Arginine Methyltransferases)

Description: Pharmacological enhancement of arginine methylation on TDP-43's RRM domains will reduce its propensity for pathological phase separation by decreasing RNA-binding avidity and promoting nuclear retention. Selective PRMT activators or arginine analogs could restore physiological TDP-43 dynamics by weakening multivalent RNA interactions that drive cytoplasmic condensation.

**Supporting Evid

🔍 Skeptic Identifies weaknesses, alternative explanations, and methodological concerns ▼

Critical Evaluation of TDP-43 Phase Separation Therapeutic Hypotheses

Hypothesis 1: Arginine Methylation Enhancement Therapy

Specific Weaknesses:

Oversimplified mechanism: The hypothesis assumes methylation uniformly reduces RNA binding, but methylation can be site-specific with variable effects on different RNA targets

Lack of specificity: PRMT1/CARM1 have numerous substrates beyond TDP-43; systemic activation could disrupt other essential methylation-dependent processes

Dosing paradox: The therapeutic window between insufficient methylation and hypermethylatio

🎯 Domain Expert Assesses practical feasibility, druggability, and clinical translation ▼

Drug Development Feasibility Assessment

TOP-TIER HYPOTHESES

Hypothesis 3: HSP70 Enhancement (Revised Confidence: 0.58)

MOST DEVELOPABLE - Clear path forward with existing compounds

Druggability Assessment: HIGH ⭐⭐⭐⭐⭐

Multiple validated approaches: Small molecule activators, gene therapy, pharmacological chaperones
Established PK/PD: HSP70 induction is measurable and dose-dependent
CNS penetration: Several HSP70 activators cross BBB effectively

Existing Chemical Matter & Clinical Pipeline:

Immediate opportunities:

Arimoclomol (ORY-2001) - O

⚖ Synthesizer Integrates perspectives and produces final ranked assessments ▼

Price History

7d Trend

↔

Stable

7d Momentum

▼ 10.5%

Volatility

Medium

0.0234

Events (7d)

⚡ Price Movement Log Recent 15 events

	Event	Price	Change	Source	Time
📄	New Evidence	$0.549	▲ 1.7%	evidence_batch_update	2026-04-13 02:18
📄	New Evidence	$0.540	▼ 6.2%	evidence_batch_update	2026-04-13 02:18
⚖	Recalibrated	$0.575	▼ 3.0%		2026-04-12 05:13
⚖	Recalibrated	$0.593	▼ 0.5%		2026-04-10 15:58
⚖	Recalibrated	$0.596	▲ 2.1%		2026-04-10 14:28
⚖	Recalibrated	$0.584	▼ 2.8%		2026-04-08 18:39
⚖	Recalibrated	$0.601	▼ 0.6%		2026-04-06 04:04
⚖	Recalibrated	$0.604	▼ 0.5%		2026-04-04 16:38
⚖	Recalibrated	$0.608	▲ 0.3%		2026-04-04 16:02
⚖	Recalibrated	$0.606	▼ 5.0%		2026-04-03 23:46
📄	New Evidence	$0.638	▲ 0.9%	evidence_batch_update	2026-04-03 01:06
📄	New Evidence	$0.632	▲ 1.1%	evidence_batch_update	2026-04-03 01:06
⚖	Recalibrated	$0.625	▲ 0.2%	market_dynamics	2026-04-03 01:06
⚖	Recalibrated	$0.624	▲ 25.3%		2026-04-02 21:55
⚖	Recalibrated	$0.498	▼ 18.6%	market_recalibrate	2026-04-02 19:14

Clinical Trials (4) Relevance: 9%

1
Active

3
Completed

0
Total Enrolled

Phase II
Highest Phase

Olaparib in Brain Metastases Phase II

Completed · NCT03462680

Veliparib CNS Pharmacokinetics Study Phase I

Completed · NCT02152982

Niraparib for CNS Metastases Phase II

Completed · NCT01434316

Talazoparib in Glioblastoma Phase I

Recruiting · NCT04297683

📚 Cited Papers (90)

PARP inhibitor resistance: the underlying mechanisms and clinical implications.

Molecular cancer (2020) · PMID:32563252

3 figures

Fig. 1

Schematic describing the function the principle of synthetic lethality interaction between PARPs and BRCA1/2. When cells suffer from DNA response, single-strand breaks emerge. PARP...

pmc_api

Fig. 2

Homologous recombination repair in S/G2 phase. The double-strand break ends are resected by MRE11-RAD50-NBS1(MRN) complex together with CtIP. ATM is recruited to DSBs through MRN a...

pmc_api

MiR223-3p promotes synthetic lethality in BRCA1-deficient cancers.

Proceedings of the National Academy of Sciences of the United States of America (2019) · PMID:31395736

6 figures

Fig. 1.

MiR223-3p down-regulates aNHEJ components PARP1, CtIP, and Pso4 in mammalian cells. ( A ) Pairing of miR223-3p to the 3′UTR region of PARP1 mRNA and CtIP mRNA, and to exon 1 of PSO...

pmc_api

Fig. 2.

MiR22-3p represses chromosomal translocation in hematopoietic cells. ( A ) QRT-PCR showing the endogenous levels of miR223-3p at different time points after Ara-C treatment in HL-6...

pmc_api

Mechanisms of PARP inhibitor sensitivity and resistance.

DNA repair (2018) · PMID:30177437

1 figure

Figures

Figures available at source paper (no open-access XML found).

deep_link

Niacin, poly(ADP-ribose) polymerase-1 and genomic stability.

Mutation research (2001) · PMID:11295153

1 figure

Figures

Figures available at source paper (no open-access XML found).

deep_link

Paper:11295153

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Paper:20181594

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Paper:23143307

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Paper:31395736

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📓 Linked Notebooks (1)

📓 TDP-43 phase separation therapeutics for ALS-FTD — Analysis Notebook

CI-generated notebook stub for analysis sda-2026-04-01-gap-006. TDP-43 undergoes liquid-liquid phase separation that becomes pathological. Small molecules targeting phase separation properties could b …

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Wiki Pages

KG Entities (38)

ALS Arginine methylation / epigenetic regula C9ORF72 CSF1R DNA_damage_response FTD G3BP1 HSP70 HSPA1A Heat shock protein / proteostasis PARP1 PARP1_protein PRMT1 Poly(ADP-ribose) polymerase / DNA damage RNA_splicing_pathway SOD1 SRPK1 SR_protein_phosphorylation Serine/arginine protein kinase / RNA spl Stress granule / RNA granule assembly

Linked Experiments (2)

DNA Damage Repair Deficiency Validation Study in Parkinson's Diseaseclinical | tests | 0.46 Regulated Necrosis Validation Study in Parkinson's Diseaseclinical | tests | 0.46

Related Hypotheses

PARP1 Inhibition Blocks Poly(PR)-Triggered DNA Damage and Subsequent p53 Activation

Score: 0.562 | neurodegeneration

Oligodendrocyte DNA Repair Enhancement

Score: 0.378 | neurodegeneration

SASP-Mediated Complement Cascade Amplification

Score: 0.703 | neurodegeneration

TREM2-Dependent Microglial Senescence Transition

Score: 0.692 | neurodegeneration

H2: Indole-3-Propionate (IPA) as the Actual Neuroprotective Effector

Score: 0.675 | neurodegeneration

Estimated Development

Estimated Cost

$35M

Timeline

5.0 years

🧪 Falsifiable Predictions (4)

4 total 0 confirmed 0 falsified

If hypothesis is true, intervention employ adaptive dosing with extensive safety monitoring, including monthly complete blood counts and annual cancer screening

pending conf: 0.50

Expected outcome: employ adaptive dosing with extensive safety monitoring, including monthly complete blood counts and annual cancer screening

Falsified by: Intervention fails to employ adaptive dosing with extensive safety monitoring, including monthly complete blood counts and annual cancer screening

If hypothesis is true, intervention serve as a diagnostic biomarker for patient selection, with elevated levels (>150 pg/mL) indicating active TDP-43 pathology suitable for intervention

pending conf: 0.50

Expected outcome: serve as a diagnostic biomarker for patient selection, with elevated levels (>150 pg/mL) indicating active TDP-43 pathology suitable for intervention

Falsified by: Intervention fails to serve as a diagnostic biomarker for patient selection, with elevated levels (>150 pg/mL) indicating active TDP-43 pathology suitable for intervention

If hypothesis is true, intervention provide early proof-of-concept evidence while functional outcomes mature

pending conf: 0.50

Expected outcome: provide early proof-of-concept evidence while functional outcomes mature

Falsified by: Intervention fails to provide early proof-of-concept evidence while functional outcomes mature

If hypothesis is true, intervention achieve brain concentrations of 100-500 nM, exceeding the IC50 values for PARP1 inhibition by 10-50-fold

pending conf: 0.50

Expected outcome: achieve brain concentrations of 100-500 nM, exceeding the IC50 values for PARP1 inhibition by 10-50-fold

Falsified by: Intervention fails to achieve brain concentrations of 100-500 nM, exceeding the IC50 values for PARP1 inhibition by 10-50-fold

Knowledge Subgraph (103 edges)

associated with (7)

HSPA1A → neurodegeneration

PARP1 → neurodegeneration

PRMT1 → neurodegeneration

G3BP1 → neurodegeneration

SRPK1 → neurodegeneration

...and 2 more

catalyzes (2)

PRMT1 → arginine_methylation_pathway

TGM2 → protein_crosslinking_pathway

co associated with (20)

HSPA1A → PARP1

HSPA1A → TGM2

HSPA1A → TARDBP

HSPA1A → SRPK1

G3BP1 → HSPA1A

...and 15 more

co discussed (49)

TGM2 → PRMT1

TGM2 → PARP1

TGM2 → HSPA1A

TGM2 → G3BP1

TGM2 → SRPK1

...and 44 more

...and 2 more

mediates (2)

PARP1_protein → DNA_damage_response

SRPK1 → SR_protein_phosphorylation

modifies (1)

arginine_methylation_pathway → TDP-43

nucleates (1)

G3BP1 → stress_granule_formation

participates in (8)

HSPA1A → Heat shock protein / proteostasis

PARP1 → Poly(ADP-ribose) polymerase / DNA damage repair

PRMT1 → Arginine methylation / epigenetic regulation

G3BP1 → Stress granule / RNA granule assembly

SRPK1 → Serine/arginine protein kinase / RNA splicing

...and 3 more

promoted: PARP1 Inhibition Therapy (1)

PARP1 → neurodegeneration

regulates (1)

TDP-43 → RNA_splicing_pathway

Mechanism Pathway for PARP1

Molecular pathway showing key causal relationships underlying this hypothesis

graph TD
    PARP1["PARP1"] -->|encodes| PARP1_protein["PARP1_protein"]
    PARP1_protein_1["PARP1_protein"] -->|mediates| DNA_damage_response["DNA_damage_response"]
    PARP1_2["PARP1"] -->|associated with| neurodegeneration["neurodegeneration"]
    PARP1_3["PARP1"] -.->|promoted: PARP1 In| neurodegeneration_4["neurodegeneration"]
    PARP1_5["PARP1"] -->|participates in| Poly_ADP_ribose__polymera["Poly(ADP-ribose) polymerase / DNA damage repair"]
    TGM2["TGM2"] -->|co discussed| PARP1_6["PARP1"]
    PRMT1["PRMT1"] -->|co discussed| PARP1_7["PARP1"]
    PARP1_8["PARP1"] -->|co discussed| HSPA1A["HSPA1A"]
    PARP1_9["PARP1"] -->|co discussed| G3BP1["G3BP1"]
    PARP1_10["PARP1"] -->|co discussed| SRPK1["SRPK1"]
    TARDBP["TARDBP"] -->|co discussed| PARP1_11["PARP1"]
    PARP1_12["PARP1"] -->|co discussed| SOD1["SOD1"]
    CSF1R["CSF1R"] -->|co discussed| PARP1_13["PARP1"]
    PARP1_14["PARP1"] -->|co discussed| TAU["TAU"]
    HSPA1A_15["HSPA1A"] -->|co discussed| PARP1_16["PARP1"]
    style PARP1 fill:#ce93d8,stroke:#333,color:#000
    style PARP1_protein fill:#4fc3f7,stroke:#333,color:#000
    style PARP1_protein_1 fill:#4fc3f7,stroke:#333,color:#000
    style DNA_damage_response fill:#81c784,stroke:#333,color:#000
    style PARP1_2 fill:#ce93d8,stroke:#333,color:#000
    style neurodegeneration fill:#ef5350,stroke:#333,color:#000
    style PARP1_3 fill:#ce93d8,stroke:#333,color:#000
    style neurodegeneration_4 fill:#ef5350,stroke:#333,color:#000
    style PARP1_5 fill:#ce93d8,stroke:#333,color:#000
    style Poly_ADP_ribose__polymera fill:#81c784,stroke:#333,color:#000
    style TGM2 fill:#ce93d8,stroke:#333,color:#000
    style PARP1_6 fill:#ce93d8,stroke:#333,color:#000
    style PRMT1 fill:#ce93d8,stroke:#333,color:#000
    style PARP1_7 fill:#ce93d8,stroke:#333,color:#000
    style PARP1_8 fill:#ce93d8,stroke:#333,color:#000
    style HSPA1A fill:#ce93d8,stroke:#333,color:#000
    style PARP1_9 fill:#ce93d8,stroke:#333,color:#000
    style G3BP1 fill:#ce93d8,stroke:#333,color:#000
    style PARP1_10 fill:#ce93d8,stroke:#333,color:#000
    style SRPK1 fill:#ce93d8,stroke:#333,color:#000
    style TARDBP fill:#ce93d8,stroke:#333,color:#000
    style PARP1_11 fill:#ce93d8,stroke:#333,color:#000
    style PARP1_12 fill:#ce93d8,stroke:#333,color:#000
    style SOD1 fill:#ce93d8,stroke:#333,color:#000
    style CSF1R fill:#ce93d8,stroke:#333,color:#000
    style PARP1_13 fill:#ce93d8,stroke:#333,color:#000
    style PARP1_14 fill:#ce93d8,stroke:#333,color:#000
    style TAU fill:#ce93d8,stroke:#333,color:#000
    style HSPA1A_15 fill:#ce93d8,stroke:#333,color:#000
    style PARP1_16 fill:#ce93d8,stroke:#333,color:#000

3D Protein Structure

🧬 PARP1 — PDB 4DQY Click to expand 3D viewer

Experimental structure from RCSB PDB | Powered by Mol* | Rotate: click+drag | Zoom: scroll | Reset: right-click

Source Analysis

TDP-43 phase separation therapeutics for ALS-FTD

neurodegeneration | 2026-04-01 | completed

PARP1 Inhibition Therapy

Hypotheses from Same Analysis (6)

Description

Mechanistic Pathway Diagram

Figures & Visualizations

3D Protein Structure

Dimension Scores

✓ Supporting Evidence 30

✗ Opposing Evidence 15

Novel Therapeutic Hypotheses for TDP-43 Phase Separation in ALS-FTD

Hypothesis 1: Arginine Methylation Enhancement Therapy

Critical Evaluation of TDP-43 Phase Separation Therapeutic Hypotheses

Hypothesis 1: Arginine Methylation Enhancement Therapy

Specific Weaknesses:

Drug Development Feasibility Assessment

TOP-TIER HYPOTHESES

Hypothesis 3: HSP70 Enhancement (Revised Confidence: 0.58)

Druggability Assessment: HIGH ⭐⭐⭐⭐⭐

Existing Chemical Matter & Clinical Pipeline:

Price History

Clinical Trials (4) Relevance: 9%

📚 Cited Papers (90)

📓 Linked Notebooks (1)

⚔ Arena Performance

Wiki Pages

KG Entities (38)

Linked Experiments (2)

Related Hypotheses

Estimated Development

🧪 Falsifiable Predictions (4)

Knowledge Subgraph (103 edges)

associated with (7)

catalyzes (2)

co associated with (20)

co discussed (49)

contributes to (1)

dysregulated in (1)

encodes (2)

implicated in (7)

mediates (2)

modifies (1)

nucleates (1)

participates in (8)

promoted: PARP1 Inhibition Therapy (1)

regulates (1)

Mechanism Pathway for PARP1

3D Protein Structure

Source Analysis

TDP-43 phase separation therapeutics for ALS-FTD