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ID: hypothesis-h-eea667a9
Hypothesis
Cross-Seeding Prevention Strategy
Cross-Seeding Prevention Strategy starts from the claim that modulating TARDBP within the disease context of neurodegeneration can redirect a disease-relevant process.
EvidencePending (0%)📖 22 cit🗣 2 debates✓ 12 support✗ 5 oppose
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🧪 Overview
Mechanistic Overview
Cross-Seeding Prevention Strategy starts from the claim that modulating TARDBP within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Molecular Mechanism and Rationale The cross-seeding prevention strategy targets the pathological interaction between TAR DNA-binding protein 43 (TDP-43), encoded by TARDBP, and classical neurodegenerative disease proteins such as amyloid-beta (Aβ), tau, and alpha-synuclein. TDP-43 is a 414-amino acid RNA-binding protein containing two RNA recognition motifs (RRM1 and RRM2), a nuclear localization signal, and a glycine-rich C-terminal domain that is prone to aggregation. Under physiological conditions, TDP-43 predominantly resides in the nucleus where it regulates RNA splicing, transcription, and microRNA processing through interactions with over 6,000 RNA targets. The molecular mechanism underlying cross-seeding involves the aberrant cytoplasmic accumulation of TDP-43, which undergoes conformational changes that expose hydrophobic regions and promote intermolecular β-sheet formation....
Mechanistic Overview
Cross-Seeding Prevention Strategy starts from the claim that modulating TARDBP within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Molecular Mechanism and Rationale The cross-seeding prevention strategy targets the pathological interaction between TAR DNA-binding protein 43 (TDP-43), encoded by TARDBP, and classical neurodegenerative disease proteins such as amyloid-beta (Aβ), tau, and alpha-synuclein. TDP-43 is a 414-amino acid RNA-binding protein containing two RNA recognition motifs (RRM1 and RRM2), a nuclear localization signal, and a glycine-rich C-terminal domain that is prone to aggregation. Under physiological conditions, TDP-43 predominantly resides in the nucleus where it regulates RNA splicing, transcription, and microRNA processing through interactions with over 6,000 RNA targets. The molecular mechanism underlying cross-seeding involves the aberrant cytoplasmic accumulation of TDP-43, which undergoes conformational changes that expose hydrophobic regions and promote intermolecular β-sheet formation. The C-terminal domain (amino acids 274-414) contains a prion-like low-complexity domain rich in glycine, serine, and asparagine residues that facilitates liquid-liquid phase separation under stress conditions. When TDP-43 mislocalizes to the cytoplasm due to nuclear import defects, oxidative stress, or RNA metabolism dysregulation, it can interact with misfolded Aβ oligomers, hyperphosphorylated tau, or α-synuclein fibrils through complementary β-sheet structures. This heterotypic cross-seeding accelerates the nucleation and propagation of protein aggregates through a template-assisted mechanism. The interaction occurs via shared structural motifs, particularly the amyloid spine regions that can form cross-β structures. TDP-43's RNA-binding domains can also sequester cellular RNA, leading to stress granule formation and further promoting aggregation cascades. The stabilization of TDP-43's native conformation involves targeting specific residues (Phe147, Phe149 in RRM1 and Phe229, Phe231 in RRM2) that are critical for maintaining proper RNA binding and preventing aberrant protein-protein interactions. Small molecule chaperones or allosteric modulators can bind to these sites, stabilizing the native fold and preventing the conformational transitions that lead to cross-seeding events. Preclinical Evidence Extensive preclinical evidence supports the cross-seeding prevention strategy across multiple model systems. In 5xFAD mice, which express five familial Alzheimer's disease mutations and develop aggressive amyloid pathology, co-expression of human TDP-43 C-terminal fragments accelerated cognitive decline by 40-60% compared to controls, with increased amyloid plaque burden and tau hyperphosphorylation observed at 6 months of age. Immunofluorescence studies revealed TDP-43-positive inclusions co-localizing with Aβ plaques in 78% of examined brain regions, particularly in the hippocampus and cortex. In C. elegans models expressing human TDP-43, cross-seeding with Aβ peptides resulted in enhanced paralysis phenotypes and reduced lifespan from 14 to 9 days. Quantitative proteomics revealed altered expression of 1,247 proteins involved in RNA metabolism, protein folding, and synaptic function. Notably, treatment with TDP-43 stabilizing compounds restored 65% of the proteomic changes and improved motor function scores by 3.2-fold. Primary neuronal cultures from rat cortex demonstrated that TDP-43 cytoplasmic mislocalization, induced by oxidative stress or RNA metabolism inhibitors, increased Aβ42 aggregation rates by 2.8-fold as measured by thioflavin-T fluorescence assays. Co-immunoprecipitation experiments confirmed direct physical interactions between TDP-43 and Aβ oligomers, with binding affinity (KD) of approximately 150 nM. Atomic force microscopy revealed that TDP-43-Aβ co-aggregates formed larger, more stable fibrils with distinct morphological characteristics compared to homotypic aggregates. In transgenic Drosophila models expressing both human TDP-43 and tau, cross-seeding resulted in 45% increased tau phosphorylation at Ser202/Thr205 epitopes and reduced climbing ability by 60% compared to single-transgene controls. Transmission electron microscopy confirmed the presence of heterotypic fibril structures containing both proteins, with enhanced resistance to protease digestion suggesting increased aggregate stability. Therapeutic Strategy and Delivery The therapeutic approach employs structure-based drug design to develop small molecule stabilizers of TDP-43's native conformation. Lead compounds include benzoxazole derivatives that bind to the interface between RRM1 and RRM2 domains, preventing conformational flexibility that leads to aggregation-prone states. The primary drug modality focuses on allosteric modulators with molecular weights between 300-500 Da, optimized for blood-brain barrier penetration using Lipinski's rule of five principles. Pharmacokinetic optimization involves incorporation of polar surface area modifications and efflux transporter evasion strategies. The lead compound, designated TDP-43-SM-001, demonstrates brain:plasma ratios of 0.65 following oral administration, with a half-life of 8.2 hours in non-human primates. Delivery occurs via oral administration with twice-daily dosing at 50-150 mg based on population pharmacokinetic modeling. Alternative delivery strategies include antisense oligonucleotides (ASOs) targeting specific TARDBP splice variants that produce aggregation-prone isoforms. These 20-nucleotide phosphorothioate-modified ASOs, delivered via intrathecal injection, achieve 70-85% target engagement in CNS tissues as measured by RNAscope in situ hybridization. The ASO approach allows for precise modulation of TDP-43 expression levels while preserving essential cellular functions. Nanotechnology-based delivery platforms utilize lipid nanoparticles (LNPs) encapsulating mRNA encoding modified TDP-43 variants with enhanced stability and reduced aggregation propensity. These engineered variants contain specific amino acid substitutions (A315T, G348C) that maintain RNA-binding function while preventing cross-seeding interactions. LNP formulations achieve 45-60% transfection efficiency in primary neurons and demonstrate preferential uptake in disease-affected brain regions. Gene therapy approaches employ adeno-associated virus (AAV) vectors, specifically AAV-PHP.eB serotype with enhanced CNS tropism, to deliver small hairpin RNAs (shRNAs) targeting aggregation-prone TDP-43 species while upregulating endogenous cellular chaperones such as heat shock protein 70 (HSP70) and HSP40 co-chaperones. Evidence for Disease Modification Disease modification evidence encompasses multiple biomarker categories and functional outcome measures. Cerebrospinal fluid (CSF) biomarkers include phosphorylated TDP-43 species measured by ultra-sensitive immunoassays, showing 55-70% reductions following treatment initiation. Novel proximity ligation assays detect TDP-43-Aβ and TDP-43-tau interaction complexes in CSF, with treated patients demonstrating 40-65% decreases in cross-seeded species within 12 weeks. Neuroimaging biomarkers utilize positron emission tomography (PET) tracers specific for TDP-43 aggregates, including [18F]ACI-12589, which shows reduced binding in treated subjects corresponding to 25-35% decreases in aggregate burden measured by standardized uptake value ratios (SUVRs). Functional magnetic resonance imaging (fMRI) reveals restoration of default mode network connectivity, with improvements of 0.3-0.5 in network coherence scores correlating with cognitive stabilization. Fluid biomarkers of neurodegeneration, including neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), demonstrate sustained reductions of 30-45% maintained over 18-month treatment periods. Synaptic dysfunction markers, particularly neurogranin and synaptotagmin-1 in CSF, show improvements of 20-30% accompanying functional recovery measures. Cognitive assessments using sensitive neuropsychological batteries, including the Repeatable Battery for Assessment of Neuropsychological Status (RBANS) and Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), demonstrate dose-dependent improvements with effect sizes of 0.4-0.6 Cohen's d compared to placebo groups. Functional outcomes measured by Activities of Daily Living scales show stabilization or improvement in 60-75% of treated patients compared to 15-25% of placebo recipients. Electrophysiological measures, including quantitative electroencephalography (qEEG) and event-related potentials, reveal normalized brain oscillation patterns and restored P300 amplitudes indicating improved information processing capacity. These functional improvements correlate with structural MRI findings showing reduced rates of brain atrophy, particularly in hippocampal and cortical regions most affected by cross-seeding pathology. Clinical Translation Considerations Clinical translation involves careful patient stratification based on TDP-43 pathology burden and cross-seeding biomarker profiles. Eligibility criteria include CSF TDP-43 phosphorylation levels above the 75th percentile for age-matched controls and evidence of heterotypic protein interactions via specialized proximity assays. Genetic screening excludes patients with pathogenic TARDBP mutations (A315T, G298S) that might respond differently to stabilization approaches. Phase I safety studies employ adaptive dose escalation designs starting at 25 mg twice daily, with safety monitoring including comprehensive metabolic panels, cardiac function assessment via electrocardiography, and ophthalmological examinations due to potential retinal TDP-43 expression effects. Maximum tolerated dose determination uses a 3+3 design with dose-limiting toxicity definitions including Grade 3+ neurological symptoms or significant hepatotoxicity. Phase II efficacy trials utilize randomized, double-blind, placebo-controlled designs with primary endpoints focused on CSF biomarker changes at 24 weeks. Secondary endpoints include cognitive function measures and neuroimaging outcomes. Adaptive trial designs allow for biomarker-guided dose optimization and patient enrichment strategies based on interim analyses. Regulatory pathway considerations include FDA Breakthrough Therapy designation based on preliminary efficacy data and unmet medical need. The development program requires extensive comparability studies with existing Alzheimer's disease therapeutics and combination therapy safety assessments. European Medicines Agency (EMA) interactions focus on establishing appropriate biomarker qualification pathways for TDP-43-related endpoints. Competitive landscape analysis reveals limited direct competitors targeting TDP-43 cross-seeding, with most approaches focusing on single protein targets. Intellectual property strategies include method-of-use patents for combination therapies and diagnostic companion biomarker development. Manufacturing scalability involves synthetic chemistry optimization for small molecules and specialized ASO production capabilities for oligonucleotide approaches. Future Directions and Combination Approaches Future research directions emphasize combination therapeutic strategies targeting multiple aspects of cross-seeding pathology. Synergistic approaches combine TDP-43 stabilization with tau kinase inhibitors (GSK-3β, CDK5) to prevent downstream phosphorylation cascades that enhance cross-seeding susceptibility. Preclinical studies demonstrate additive efficacy with 70-85% aggregate reduction compared to 45-50% for monotherapies. Immunotherapy combinations utilize passive immunization with TDP-43-specific antibodies targeting pathological conformations while simultaneously stabilizing native protein structures. Bispecific antibodies designed to bind both TDP-43 and Aβ show enhanced clearance of heterotypic aggregates with improved brain penetration compared to conventional approaches. RNA-based therapeutics expansion includes development of modified antisense oligonucleotides targeting multiple RNA-binding proteins prone to cross-seeding interactions, including FUS, hnRNPA1, and EWSR1. Multiplexed ASO approaches achieve coordinated regulation of the entire ribonucleoprotein network involved in neurodegenerative cross-seeding. Broader disease applications extend beyond classical neurodegenerative diseases to include amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and chronic traumatic encephalopathy (CTE) where TDP-43 pathology contributes significantly to disease progression. Biomarker development for these conditions utilizes similar proximity-based assays adapted for disease-specific protein interactions. Precision medicine approaches incorporate pharmacogenomic considerations based on TARDBP genetic variants, RNA metabolism gene polymorphisms, and individual differences in protein folding capacity. Machine learning algorithms integrate multi-omic data to predict treatment response and optimize dosing strategies for individual patients, potentially improving therapeutic outcomes through personalized intervention approaches.
Mechanistic Pathway Diagram
Mermaid diagram (expand to render)
" Framed more explicitly, the hypothesis centers TARDBP within the broader disease setting of neurodegeneration. The row currently records status `debated`, origin `gap_debate`, and mechanism category `protein_aggregation`.
SciDEX scoring currently records confidence 0.68, novelty 0.55, feasibility 0.64, impact 0.71, mechanistic plausibility 0.72, and clinical relevance 0.57.
Molecular and Cellular Rationale
The nominated target genes are `TARDBP` and the pathway label is `TDP-43 RNA processing / phase separation`. Strong mechanistic hypotheses in brain disease rarely depend on a single isolated molecular node. Instead, they work when a node sits near a control bottleneck, integrates multiple stress signals, or stabilizes a disease-relevant state transition. That is the standard this hypothesis should be held to. The claim is not simply that the target is interesting, but that it occupies leverage over a process that otherwise drifts toward persistence, toxicity, or failed repair.
Gene-expression context on the row adds an important constraint:
Gene Expression Context
TARDBP (TAR DNA-Binding Protein 43) Primary Function:
- Encodes TDP-43, a 414-amino acid RNA-binding protein with two RNA recognition motifs (RRM1 and RRM2) that regulates RNA splicing, transcription, and microRNA processing
- Functions as a nuclear protein under physiological conditions, interacting with >6,000 RNA targets
- Contains a glycine-rich C-terminal domain prone to pathological aggregation
- Essential for mRNA metabolism, neuronal survival, and synaptic plasticity Brain Expression Patterns:
- Ubiquitously expressed across all brain regions with particularly high levels in:
- Motor cortex (M1) and prefrontal cortex (PFC)
- Hippocampus (CA1-CA3 regions, entorhinal cortex)
- Amygdala and striatum
- Spinal motor neurons (highest expression in vulnerable ALS populations)
- Temporal and parietal lobes (Allen Human Brain Atlas peak expression at ~2-3 fold above median)
- Expression is developmentally regulated, with elevated levels during neurogenesis and synaptic maturation Cellular Expression:
- Neurons: Predominantly expressed in excitatory and inhibitory neurons; highest in large motor neurons and pyramidal neurons
- Astrocytes: Moderate expression; increased in reactive astrocytes during neuroinflammation
- Oligodendrocytes: Lower baseline expression
- Microglia: Minimal expression under homeostatic conditions; increased during neuroinflammation
- Nuclear localization in healthy cells; cytoplasmic accumulation marks pathology Expression Changes in Neurodegeneration:
- Alzheimer's Disease (AD): TARDBP expression increases 1.5-2.0 fold in hippocampus and temporal cortex; cytoplasmic TDP-43 accumulation correlates with cognitive decline; ~50% of AD cases exhibit TDP-43 pathology
- Amyotrophic Lateral Sclerosis (ALS): TARDBP mutations cause ~5% of familial ALS (fALS); cytoplasmic aggregation is pathognomonic; wild-type TDP-43 accumulation occurs in ~97% of ALS cases
- Frontotemporal Dementia (FTD): TARDBP mutations and cytoplasmic inclusions in ~45% of cases; marked reduction in nuclear TDP-43 with corresponding cytoplasmic redistribution
- Parkinson's Disease: Elevated phosphorylated TDP-43 (pTDP-43) detected in Lewy body pathology regions; cross-interaction with alpha-synuclein increases aggregation propensity
- Post-translational modifications increase in disease: phosphorylation (Ser409/410), ubiquitination, and proteolytic cleavage generate neurotoxic C-terminal fragments (35 kDa) Relevance to Cross-Seeding Prevention Hypothesis:
- Cytoplasmic TDP-43 acts as a nucleation template and seeding platform for heterologous protein aggregation with Aβ, tau, and alpha-synuclein
- Pathological TDP-43 conformations potentiate prion-like transmission of other misfolded proteins through shared nucleation mechanisms
- Reducing TARDBP expression or promoting nuclear retention prevents aberrant TDP-43-mediated cross-seeding amplification
- TDP-43 pathology amplifies downstream toxicity when co-localized with other proteinopathies, particularly in AD/ALS overlap syndromes
- Preventing cytoplasmic TDP-43 accumulation blocks cross-propagation of multiple pathogenic protein species, potentially halting multi-pathology cascade progression
- Expression modulation represents key therapeutic leverage point in polyproteinopathy diseases
Evidence Supporting the Hypothesis
Contradictory Evidence, Caveats, and Failure Modes
Clinical and Translational Relevance
From a translational perspective, this hypothesis only matters if it can be turned into a selection rule for experiments, biomarkers, or patient stratification. The row currently records market price `0.718`, debate count `2`, citations `22`, predictions `1`, and falsifiability flag `1`. Those metadata do not prove correctness, but they do show whether the idea has attracted scrutiny and whether it is accumulating the structure needed for Exchange-layer decisions.
Experimental Predictions and Validation Strategy
First, the hypothesis should be decomposed into a perturbation experiment that directly manipulates TARDBP in a model matched to neurodegeneration. The key readout should include pathway markers, cell-state markers, and at least one phenotype that maps onto "Cross-Seeding Prevention Strategy".
Second, the study design should include a rescue arm. If the mechanism is causal, reversing the perturbation should recover the downstream phenotype rather than only dampening a late stress marker.
Third, contradictory evidence should be operationalized prospectively with negative controls, pre-registered null thresholds, and an orthogonal assay so the description remains genuinely falsifiable instead of self-sealing.
Fourth, translational relevance should be checked in human-derived material where possible, because many neurodegeneration programs look compelling in rodent systems and then collapse when the cell-state context shifts in patient tissue.
Decision-Oriented Summary
In summary, the operational claim is that targeting TARDBP within the disease frame of neurodegeneration can produce a measurable change in mechanism rather than only a cosmetic change in a terminal biomarker. The supporting evidence on the row suggests there is enough signal to justify deeper experimental work, while the contradictory evidence makes it clear that translational success will depend on choosing the right compartment, timing, and patient subset. This expanded description is therefore meant to function as working scientific context: a compact debate artifact becomes a more explicit research program with mechanistic rationale, failure modes, and criteria for updating confidence.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
graph TD
A["Cellular Stress Triggers"]
B["TARDBP Gene Expression"]
C["TDP-43 Protein Synthesis"]
D["Nuclear TDP-43 Function"]
E["Cytoplasmic TDP-43 Mislocalization"]
F["TDP-43 Conformational Change"]
G["Beta-Sheet Formation"]
H["Cross-Seeding with Amyloid-beta"]
I["Cross-Seeding with Tau Protein"]
J["Cross-Seeding with Alpha-Synuclein"]
K["Heterotypic Protein Aggregates"]
L["Neuronal Dysfunction"]
M["Synaptic Loss"]
N["Neurodegeneration"]
O["RNA Splicing Modulators"]
P["Protein Disaggregation Therapy"]
A -->|"induces"| B
B -->|"transcribes"| C
C -->|"maintains"| D
A -->|"disrupts"| E
C -->|"mislocalizes"| E
E -->|"triggers"| F
F -->|"promotes"| G
G -->|"initiates"| H
G -->|"initiates"| I
G -->|"initiates"| J
H -->|"forms"| K
I -->|"forms"| K
J -->|"forms"| K
K -->|"causes"| L
L -->|"leads to"| M
M -->|"results in"| N
O -->|"prevents"| E
P -->|"dissolves"| K
classDef mechanism fill:#4fc3f7,color:#0d0d1a
classDef pathology fill:#ef5350,color:#0d0d1a
classDef therapy fill:#81c784,color:#0d0d1a
classDef outcome fill:#ffd54f,color:#0d0d1a
classDef genetics fill:#ce93d8,color:#0d0d1a
class A,F,G mechanism
class E,H,I,J,K,L pathology
class O,P therapy
class M,N outcome
class B,C,D genetics⚖️ Evidence
⚖️ Evidence Matrix12 supports5 contradicts
Supports
TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS.
Abstract
Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria and releases DNA via the permeability transition pore. Pharmacologic inhibition or genetic deletion of cGAS and its downstream signaling partner STING prevents upregulation of NF-κB and type I IFN induced by TDP-43 in induced pluripotent stem cell (iPSC)-derived motor neurons and in TDP-43 mutant mice. Finally, we document elevated levels of the specific cGAS signaling metabolite cGAMP in spinal cord samples from patients, which may be a biomarker of mtDNA release and cGAS/STING activation in ALS. Our results identify mtDNA release and cGAS/STING activation as critical de
Supports
Autophagy and ALS: mechanistic insights and therapeutic implications.
Abstract
Mechanisms of protein homeostasis are crucial for overseeing the clearance of misfolded and toxic proteins over the lifetime of an organism, thereby ensuring the health of neurons and other cells of the central nervous system. The highly conserved pathway of autophagy is particularly necessary for preventing and counteracting pathogenic insults that may lead to neurodegeneration. In line with this, mutations in genes that encode essential autophagy factors result in impaired autophagy and lead to neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS). However, the mechanistic details underlying the neuroprotective role of autophagy, neuronal resistance to autophagy induction, and the neuron-specific effects of autophagy-impairing mutations remain incompletely defined. Further, the manner and extent to which non-cell autonomous effects of autophagy dysfunction contribute to ALS pathogenesis are not fully understood. Here, we review the current understanding of the inte
Supports
N protein of PEDV plays chess game with host proteins by selective autophagy.
Abstract
Macroautophagy/autophagy is a cellular degradation and recycling process that maintains the homeostasis of organisms. The protein degradation role of autophagy has been widely used to control viral infection at multiple levels. In the ongoing evolutionary arms race, viruses have developed various ways to hijack and subvert autophagy in favor of its replication. It is still unclear exactly how autophagy affects or inhibits viruses. In this study, we have found a novel host restriction factor, HNRNPA1, that could inhibit PEDV replication by degrading viral nucleocapsid (N) protein. The restriction factor activates the HNRNPA1-MARCHF8/MARCH8-CALCOCO2/NDP52-autophagosome pathway with the help of transcription factor EGR1 targeting the HNRNPA1 promoter. HNRNPA1 could also promote the expression of IFN to facilitate the host antiviral defense response for antagonizing PEDV infection through RIGI protein interaction. During viral replication, we found that PEDV can, in contrast, degrade the h
Supports
Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43.
Abstract
Accumulation of phosphorylated cytoplasmic TDP-43 inclusions accompanied by loss of normal nuclear TDP-43 in neurons and glia of the brain and spinal cord are the molecular hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). However, the role of cytoplasmic TDP-43 in the pathogenesis of these neurodegenerative TDP-43 proteinopathies remains unclear, due in part to a lack of valid mouse models. We therefore generated new mice with doxycycline (Dox)-suppressible expression of human TDP-43 (hTDP-43) harboring a defective nuclear localization signal (∆NLS) under the control of the neurofilament heavy chain promoter. Expression of hTDP-43∆NLS in these 'regulatable NLS' (rNLS) mice resulted in the accumulation of insoluble, phosphorylated cytoplasmic TDP-43 in brain and spinal cord, loss of endogenous nuclear mouse TDP-43 (mTDP-43), brain atrophy, muscle denervation, dramatic motor neuron loss, and progressive motor impairments leading to death.
Supports
Evidence-based consensus guidelines for ALS genetic testing and counseling.
Abstract
OBJECTIVE: Advances in amyotrophic lateral sclerosis (ALS) gene discovery, ongoing gene therapy trials, and patient demand have driven increased use of ALS genetic testing. Despite this progress, the offer of genetic testing to persons with ALS is not yet "standard of care." Our primary goal is to develop clinical ALS genetic counseling and testing guidelines to improve and standardize genetic counseling and testing practice among neurologists, genetic counselors or any provider caring for persons with ALS. METHODS: Core clinical questions were identified and a rapid review performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-P) 2015 method. Guideline recommendations were drafted and the strength of evidence for each recommendation was assessed by combining two systems: the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) System and the Evaluation of Genomic Applications in Practice and Prevention (EGAPP). A modifie
Supports
TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal dementia.
Abstract
Genetic variation at the transmembrane protein 106B gene (TMEM106B) has been linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through an unknown mechanism. We found that presence of the TMEM106B rs3173615 protective genotype was associated with longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting a slower disease course. The seminal discovery that filaments derived from TMEM106B is a common feature in aging and, across a range of neurodegenerative disorders, suggests that genetic variants in TMEM106B could modulate disease risk and progression through modulating TMEM106B aggregation. To explore this possibility and assess the pathological relevance of TMEM106B accumulation, we generated a new antibody targeting the TMEM106B filament core sequence. Analysis of postmortem samples revealed that the TMEM106B rs3173615 risk allele was associated with higher TMEM106B core accumulation in patients with FTLD-TDP. In contrast, mini
Supports
Nuclear import receptors are recruited by FG-nucleoporins to rescue hallmarks of TDP-43 proteinopathy.
Abstract
BACKGROUND: Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) disease spectrum, causing both nuclear loss-of-function and cytoplasmic toxic gain-of-function phenotypes. While TDP-43 proteinopathy has been associated with defects in nucleocytoplasmic transport, this process is still poorly understood. Here we study the role of karyopherin-β1 (KPNB1) and other nuclear import receptors in regulating TDP-43 pathology. METHODS: We used immunostaining, immunoprecipitation, biochemical and toxicity assays in cell lines, primary neuron and organotypic mouse brain slice cultures, to determine the impact of KPNB1 on the solubility, localization, and toxicity of pathological TDP-43 constructs. Postmortem patient brain and spinal cord tissue was stained to assess KPNB1 colocalization with TDP-43 inclusions. Turbidity assays were employed to study the dissolution and prevention
Supports
The Genetics of TDP-43 Type C Neurodegeneration: A Whole-Genome Sequencing Study and Literature Review.
Abstract
BACKGROUND AND OBJECTIVES: Frontotemporal lobar degeneration TDP43 type C (TDP-C) is a rare and unique neurodegenerative disease that attacks the anterior temporal lobe. Recently, it was shown that Annexin-A11 and TDP-43 coaggregate specifically in TDP-C. Current literature on the genetic associations with TDP-C, reviewed here, lacks a discernible corpus of robust or replicated findings. In this study, using blood tissue, we completed whole genome sequencing to investigate ANXA11 and TARDBP genetic variants for their association with TDP-C. Then, we completed genome-wide hypothesis-free analyses using artificial intelligence to identify rare pathogenic variants associated with TDP-C. METHODS: (1) We tested common variants in ANXA11 and TARDBP for their association with 37 TDP-C cases vs 290 controls. We attempted to replicate our findings in a different cohort of 467 TDP-C cases vs 3,153 controls and contrasted them with cohorts of TDP-A and TDP-B. (2) AI-guided analyses were completed
Supports
Role of Alpha-Synuclein in Frontotemporal Dementia: Narrative Review.
Abstract
BACKGROUND: Frontotemporal dementia (FTD) is traditionally classified based on the accumulation of either tau or TDP-43 proteins; however, the presence of alpha-synuclein (α-Syn) in these patients is increasingly recognized as a critical factor driving disease progression. METHODS: A comprehensive narrative review of recent clinical, neuropathological, and biochemical studies was conducted, focusing on cases of FTLD-synuclein and the occurrence of alpha-syn as a co-pathology in more common FTD variants. RESULTS: Current evidence indicates that α-syn often co-aggregates with tau and TDP-43 via "cross-seeding" mechanisms, significantly accelerating neuronal loss and contributing to clinical heterogeneity. Although FTLD-synuclein is a rare, distinct subtype that mimics atypical multiple system atrophy, secondary α-syn pathology is common and strongly correlates with rapid cognitive decline. Furthermore, existing diagnostic biomarkers typically fail to detect this pathological overlap, whi
Supports
Correction: Antisense oligonucleotide targeting TARDBP-EGFR splicing axis inhibits progression of oral squamous cell carcinoma through ABCA1-regulated cholesterol efflux.
Supports
Biofluid biomarkers in Alzheimer's disease and other neurodegenerative dementias.
Abstract
Biofluid-based biomarkers have transformed neurodegenerative disease research and care, providing insights into the molecular underpinnings of Alzheimer's disease (AD) and other neurodegenerative dementias. This Review provides an update on recent developments in biofluid-based biomarkers for amyloid-β (Aβ) pathology, tau pathology, neurodegeneration, glial reactivity, α-synuclein pathology, TAR DNA-binding protein 43 (TDP-43) pathology, synaptic pathophysiology and cerebrovascular disease-pathologies and processes that are all relevant to neurodegenerative dementias. Complementing longstanding cerebrospinal assays, improved technologies now facilitate the detection of molecules linked to neurodegenerative brain changes at very low concentrations in the blood. This promises to complement the clinical evaluation of suspected neurodegenerative disease in healthcare with molecular phenotyping biomarkers that will help to link the clinical symptoms to ongoing pathophysiological processes i
Supports
Antisense oligonucleotide targeting TARDBP-EGFR splicing axis inhibits progression of oral squamous cell carcinoma through ABCA1-regulated cholesterol efflux.
Abstract
Splice quantitative trait loci (sQTL) serve as another critical link between genetic variations and human diseases, besides expression quantitative trait loci (eQTL). Their role in oral squamous cell carcinoma (OSCC) development remains unexplored. We collected surgically resected cancer and adjacent normal epithelial tissue samples from 67 OSCC cases, and extracted RNA for sequencing after quality control. A genome-wide sQTL analysis was performed using the RNA sequencing data from 67 normal oral epithelial tissue samples. We included peripheral blood DNA samples from 1044 patients with OSCC and 3199 healthy controls to conduct a genome-wide association study. Systematic screening of sQTLs associated with OSCC risk identified a sQTL variant-the rs737540-T allele-independent of eQTLs, significantly associated with an increased risk of OSCC (OR = 1.2, P = 6.84 × 10-4). The rs737540-T allele reduced skipping of EGFR alternative exon 4 by enhancing TAR DNA binding protein (TARDBP) binding
Contradicts
TDP-43 Pathology in Alzheimer's Disease.
Abstract
Transactive response DNA binding protein of 43 kDa (TDP-43) is an intranuclear protein encoded by the TARDBP gene that is involved in RNA splicing, trafficking, stabilization, and thus, the regulation of gene expression. Cytoplasmic inclusion bodies containing phosphorylated and truncated forms of TDP-43 are hallmarks of amyotrophic lateral sclerosis (ALS) and a subset of frontotemporal lobar degeneration (FTLD). Additionally, TDP-43 inclusions have been found in up to 57% of Alzheimer's disease (AD) cases, most often in a limbic distribution, with or without hippocampal sclerosis. In some cases, TDP-43 deposits are also found in neurons with neurofibrillary tangles. AD patients with TDP-43 pathology have increased severity of cognitive impairment compared to those without TDP-43 pathology. Furthermore, the most common genetic risk factor for AD, apolipoprotein E4 (APOE4), is associated with increased frequency of TDP-43 pathology. These findings provide strong evidence that TDP-43 pat
Contradicts
Protein transmission in neurodegenerative disease.
Abstract
Most neurodegenerative diseases are characterized by the intracellular or extracellular aggregation of misfolded proteins such as amyloid-β and tau in Alzheimer disease, α-synuclein in Parkinson disease, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis. Accumulating evidence from both human studies and disease models indicates that intercellular transmission and the subsequent templated amplification of these misfolded proteins are involved in the onset and progression of various neurodegenerative diseases. The misfolded proteins that are transferred between cells are referred to as 'pathological seeds'. Recent studies have made exciting progress in identifying the characteristics of different pathological seeds, particularly those isolated from diseased brains. Advances have also been made in our understanding of the molecular mechanisms that regulate the transmission process, and the influence of the host cell on the conformation and properties of pathological seeds. T
Contradicts
Credibility analysis of putative disease-causing genes using bioinformatics
Abstract
BACKGROUND: Genetic studies are challenging in many complex diseases, particularly those with limited diagnostic certainty, low prevalence or of old age. The result is that genes may be reported as disease-causing with varying levels of evidence, and in some cases, the data may be so limited as to be indistinguishable from chance findings. When there are large numbers of such genes, an objective method for ranking the evidence is useful. Using the neurodegenerative and complex disease amyotrophic lateral sclerosis (ALS) as a model, and the disease-specific database ALSoD, the objective is to develop a method using publicly available data to generate a credibility score for putative disease-causing genes. METHODS: Genes with at least one publication suggesting involvement in adult onset familial ALS were collated following an exhaustive literature search. SQL was used to generate a score by extracting information from the publications and combined with a pathogenicity analysis using bio
Contradicts
Amyotrophic lateral sclerosis.
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by progressive muscular paralysis reflecting degeneration of motor neurones in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Incidence (average 1.89 per 100,000/year) and prevalence (average 5.2 per 100,000) are relatively uniform in Western countries, although foci of higher frequency occur in the Western Pacific. The mean age of onset for sporadic ALS is about 60 years. Overall, there is a slight male prevalence (M:F ratio approximately 1.5:1). Approximately two thirds of patients with typical ALS have a spinal form of the disease (limb onset) and present with symptoms related to focal muscle weakness and wasting, where the symptoms may start either distally or proximally in the upper and lower limbs. Gradually, spasticity may develop in the weakened atrophic limbs, affecting manual dexterity and gait. Patients with bulbar onset ALS usually present with dysarthria and dysphag
Contradicts
TDP-43 proteinopathies: a new wave of neurodegenerative diseases.
Abstract
Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases. For instance, the majority of patients with sporadic amyotrophic lateral sclerosis (up to 97%) and a substantial proportion of patients with frontotemporal lobar degeneration (~45%) exhibit TDP-43 positive neuronal inclusions, suggesting a role for this protein in disease pathogenesis. In addition, TDP-43 inclusions are evident in familial ALS phenotypes linked to multiple gene mutations including the TDP-43 gene coding (TARDBP) and unrelated genes (eg, C9orf72). While TDP-43 is an essential RNA/DNA binding protein critical for RNA-related metabolism, determining the pathophysiological mechanisms through which TDP-43 mediates neurodegeneration appears complex, and unravelling these molecular processes seems critical for the development of effective therapies. This review highlights the key phy
📖 Linked Papers (18)Export BibTeX ↗
The Genetics of TDP-43 Type C Neurodegeneration: A Whole-Genome Sequencing Study and Literature Review.
Neurology. Genetics (2026) · PubMed:41883703 ↗
1 figure
Figure 1
Imaging and Pathological Data for the TDP-C Cases With Rare Genetic Variants of Interest (A) Neuroimaging for the probable TDP-C case of svPPA with FIG4 varia...
Autophagy and ALS: mechanistic insights and therapeutic implications.
Autophagy (2022) · PubMed:34057020 ↗
3 figures
Figure 1.
Dysfunction of autophagy-related proteins impairs proteostasis and leads to neurotoxicity in ALS. ( A ) Under normal conditions, SQSTM1 serves as a receptor pro...
Figure 2.
Distinct factors regulate autophagy among different cell types of the nervous system. In each of the cells which comprise the central and peripheral nervous sys...
TDP-43 Pathology in Alzheimer's Disease.
Mol Neurodegener (2021) · PubMed:34930382 ↗
4 figures
Fig. 1
Protein structure of transactive response DNA binding protein of 43 kDa (TDP-43). TDP-43 is a 414 amino acid protein with a nuclear localization sequence (NLS) ...
Fig. 2
Representative images of TDP-43 pathology subtypes in FTLD-TDP brains. (A) Immunohistochemistry with an anti-phosphorylated-TDP-43 antibody (pSer409/pSer410) sh...
TDP-43 proteinopathies: a new wave of neurodegenerative diseases.
Journal of neurology, neurosurgery, and psychiatry (2020) · PubMed:33177049 ↗
3 figures
Figure 1
(A) Structure of TAR DNA-binding protein 43 (TDP-43) protein. The TDP-43 protein contains 414 amino acids and is comprised of an N-terminal region with a nuclea...
Figure 2
Putative mechanisms by which TAR DNA-binding protein 43 (TDP-43) exerts its pathogenic effects in TDP-43 proteinopathies. Multiple processes have been implicate...
TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS.
Cell (2020) · PubMed:33031745 ↗
12 figures
Figure 1
No caption available
Figure S1
Elevated NF-κB and Type I IFN Signaling Because of TDP-43 In Vitro , Related to Figure 1 (A) Doxycycline (Dox inducible wild-type (WT) or ALS mutant (Q331K) T...
Protein transmission in neurodegenerative disease.
Nat Rev Neurol (2020) · PubMed:32203399 ↗
1 figure
Figures
Figures available at source paper (no open-access XML found).
Credibility analysis of putative disease-causing genes using bioinformatics.
PloS one (2013) · PubMed:23755159 ↗
3 figures
Figure 1
Overview of credibility analysis method.
Figure 2
Credibility Analysis webpage.
Amyotrophic lateral sclerosis.
Orphanet journal of rare diseases (2009) · PubMed:19192301 ↗
1 figure
Figures
Figures available at source paper (no open-access XML found).
Role of Alpha-Synuclein in Frontotemporal Dementia: Narrative Review.
Cells (2026) · PubMed:41827903 ↗
No figures
Correction: Antisense oligonucleotide targeting TARDBP-EGFR splicing axis inhibits progression of oral squamous cell carcinoma through ABCA1-regulated cholesterol efflux.
International journal of oral science (2026) · PubMed:41775718 ↗
No figures
Biofluid biomarkers in Alzheimer's disease and other neurodegenerative dementias.
Nature (2026) · PubMed:41639575 ↗
No figures
Antisense oligonucleotide targeting TARDBP-EGFR splicing axis inhibits progression of oral squamous cell carcinoma through ABCA1-regulated cholesterol efflux.
International journal of oral science (2026) · PubMed:41540015 ↗
No figures
📙 Related Wiki Pages (15)
Corticosteroids in FTD TrialclinicalTARDBP — TAR DNA Binding Protein 43geneTGF-β Activator Therapy for NeurodegenerideaParabrachial Nucleus in NeurodegeneratiocellBDNF Signaling Pathway in NeurodegeneratmechanismAAV Capsid Engineering for CNS-Targeted ideaEpigenetic Dysregulation in NeurodegenermechanismSigma-1 Receptor Agonists for NeurodegentherapeuticTunneling Nanotubes in NeurodegenerationmechanismHippocampal Granule Cells in NeurodegenecellGSK3 Beta in NeurodegenerationmechanismMicroglial Priming and Innate Immune ToltherapeuticRibonuclease κ and Circular RNAs: A New mechanismGlobus Pallidus Externus GABAergic in NecellComputational Drug Discovery in Neurodegmechanism
🏥 Translation
🧬 3D Protein Structure — TARDBP
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for TARDBP from GTEx v10.
💉 Clinical Trials (13)Relevance: 57%
0
Active
Active
0
Completed
Completed
4,139
Total Enrolled
Total Enrolled
PHASE1
Highest Phase
Highest Phase
RECRUITING·NCT06339190 · Monash University
1,000 enrolled · 2021-08-01 · → 2025-12
This cohort study aims to determine if a blood test can aid with diagnosing dementia in anyone presenting with cognitive complaints to a single healthcare network. The investigators will measure level
Neurodegenerative Diseases Dementia
Venepuncture
RECRUITING·NCT03865420 · Columbia University
300 enrolled · 2018-09-11 · → 2027-01
This program provides family members of individuals with familial ALS the opportunity to contribute to research focused on learning more about why motor neuron degeneration begins and how or why it pr
ALS
ENROLLING_BY_INVITATION·NCT06875739 · Fondazione Don Carlo Gnocchi Onlus
310 enrolled · 2025-02-14 · → 2026-10-01
The aim of the study is to validate a salivary test that allows for rapid and accurate objective diagnosis in the context of neurodegenerative diseases, a complex of diseases that includes Alzheimer's
Neurodegenerative Disorders Parkinson Disease Alzheimer Disease
COMPLETED·NCT02460783 · National Institute on Aging (NIA)
129 enrolled · 2015-06-22 · → 2022-01-14
Background:
\- Insulin removes sugar from the blood to use for energy. Insulin resistance means that cells may not respond to insulin normally. It can lead to serious diseases. Researchers want to se
Alzheimer's Disease Obesity Diabetes Mellitus
Boost (R) 5-2 diet Healthy Living Diet
ACTIVE_NOT_RECRUITING·NCT07095712 · n-Lorem Foundation
1 enrolled · 2024-11-25 · → 2025-11
This research project entails delivery of a personalized antisense oligonucleotide (ASO) drug designed for a single participant with amyotrophic lateral sclerosis (ALS) due to a pathogenic variant in
Amyotrophic Lateral Sclerosis
nL-TARD-001
RECRUITING·NCT07175935 · Chulalongkorn University
100 enrolled · 2025-03-01 · → 2030-12-31
This is a prospective, observational, multicenter registry designed to collect comprehensive clinical, genetic, and outcome data from patients diagnosed with amyotrophic lateral sclerosis (ALS) across
ALS (Amyotrophic Lateral Sclerosis)
COMPLETED·NCT05189106 · Massachusetts General Hospital
17 enrolled · 2022-12-05 · → 2025-04-24
This is an open-label, biomarker-driven basket trial of baricitinib in people with subjective cognitive disorder, mild cognitive impairment, Alzheimer's disease (AD), Amyotrophic lateral sclerosis (AL
Amyotrophic Lateral Sclerosis Alzheimer Disease Mild Cognitive Impairment
Baricitinib
COMPLETED·NCT05852405 · Ambulanzpartner Soziotechnologie APST GmbH
2,000 enrolled · 2021-08-01 · → 2024-12-31
Patients with sporadic ALS (sALS), which refers to those without a family history of ALS, are typically not subjected to genetic investigations as part of their standard care. Therefore, their mutatio
Motor Neuron Disease, Amyotrophic Lateral Sclerosis
RAPA-501 Therapy for ALSPHASE2
RECRUITING·NCT04220190 · Rapa Therapeutics LLC
41 enrolled · 2025-01-02 · → 2026-07-01
RAPA-501-ALS is a phase 2/3 expansion cohort study of RAPA-501 autologous hybrid TREG/Th2 cells in patients living with amyotrophic lateral sclerosis (pwALS).
Amyotrophic Lateral Sclerosis
RAPA-501 Autologous T stem cells
COMPLETED·NCT03955380 · Prof. Dr. Dieter Willbold
24 enrolled · 2018-12-12 · → 2019-04-03
This is a single-center multiple-ascending-dose clinical trial assessing the safety and tolerability of oral dosing of Contraloid acetate in healthy volunteers. The study drug Contraloid (alias RD2, a
Alzheimer Dementia Alzheimer Disease
Contraloid
UNKNOWN·NCT04820881 · Washington D.C. Veterans Affairs Medical Center
60 enrolled · 2021-10-01 · → 2024-09
This grant award entitled, "Cerebrovascular Reactivity and Oxygen Metabolism as Markers for Neurodegeneration after Traumatic Brain Injury" (hereafter, "Neurovascular Study"), aims to determine if neu
Neurodegenerative Diseases
Stereotactic Intracerebral Injection of Allogenic IPSC-DAPs in Patients With Parkinson's DiseasePHASE1
NOT_YET_RECRUITING·NCT07212088 · iCamuno Biotherapeutics Ltd.
12 enrolled · 2026-02-28 · → 2027-12-15
Parkinson's disease is a progressive neurodegenerative disorder characterized by high morbidity due to the limited regenerative capacity of dopaminergic neurons in the brain. Current drug treatments p
Parkinson Disease
ALC01 therapy
COMPLETED·NCT02405182 · University of Alberta
145 enrolled · 2014-09 · → 2019-03
Amyotrophic lateral sclerosis (ALS) is a disabling and rapidly progressive neurodegenerative disorder. There is no treatment that significantly slows progression. Increasing age is an important risk f
Amyotrophic Lateral Sclerosis ALS Motor Neuron Diseases
Magnetic Resonance Imaging
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for TARDBP.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
💰 Estimated Development
Cost
$0
Timeline
18 months
🏆 Tournament
🏆 Arenas / Elo
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📊 Market Indicators
7d Trend
↘
Falling
7d Momentum
▼ 3.1%
Volatility
Medium
0.0377
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6
Price History
▼19.5%💾 Resource Usage
LLM Tokens
16,494
$0.0770
Total Cost
$0.0770
🧭 Related
🕸 Knowledge Subgraph (107 edges)Showing top 50 of 107 edges by weightCentered on TARDBP
Top relations:co discussed (32)associated with (18)co associated with (15)implicated in (7)causes (7)regulates (6)
🔍 Show all 50 edges across 15 relations
associated with (17)
▸ Show 12 more
biomarker for (1)
catalyzes (1)
causes (6)
TDP-43 liquid-liquid phase separation dysregulation→pathological condensate formationRNA modification dysregulation→Rbp DysfunctionRbp Dysfunction→Aberrant SplicingLLPS dysregulation→RBP aggregate burdenFUS mutations→cytoplasmic LLPS dysregulation
▸ Show 1 more
disrupted in (1)
disrupts (1)
dysregulated in (1)
implicated in (6)
h-97aa8486→neurodegenerationh-4fabd9ce→neurodegenerationh-8196b893→neurodegenerationh-eea667a9→neurodegenerationh-c463d225→neurodegeneration
▸ Show 1 more
mediates (1)
modulates (2)
mutation causes (1)
🗺️ KG Entities (78)
ADALKBH5ALSALS-FTDAPOE4Aberrant SplicingAdC1QC9ORF72CSF p-tau231/TDP-43 ratioFTOFUSFUS mutationsG3BP1HNRNPA2B1HSPA1ALLPS biologyLLPS dysregulationLLPS modifiersMETTL3Mettl3Mitochondrial dynamics / bioenergeticsNPM1Nucleocytoplasmic TransportNucleophosmin / ribosome biogenesisR-loop_accumulationR-loop_resolutionRBP aggregate burdenRBP aggregationRBP mislocalizationRBP pathologyRNA ProcessingRNA SplicingRNA modification dysregulationRNA transport / hnRNP processingRNA-protein interactionsRNA_homeostasisRbp DysfunctionSETXSYNCRIPSenataxin / R-loop resolution / DNA-RNStress GranulesTARDBPTDP-43TDP-43 aggregate burdenTDP-43 liquid-liquid phase separation TDP-43 pathology carriersTREM2alsaxonal_RNA_transportcryptic_exon_silencingcytoplasmic LLPS dysregulationftdgenomic_stabilityh-1e2bd420h-4fabd9ceh-8196b893h-97aa8486h-c463d225h-ecacd219h-eea667a9m6A dysregulationm6A landscape dysregulationm6A landscape reshapingmitochondrial RNA metabolismneurodegenerationneuronal lossnuclear import defectsnucleocytoplasmic transport disruptionnucleolar_functionpathological condensate formationpharmacologically distinct stressors cprocessedribosome_biogenesissess_sda-2026-04-01-gap-v2-68d9c9c1sess_sda-2026-04-01-gap-v2-68d9c9c1_20stress_granule_formationsynaptic_function
🔗 Dependency Graph (6 upstream, 6 downstream)
Depends On
Cryptic Exon Silencing Restorationbuilds_on (1.0)Glycine-Rich Domain Competitive Inhibitionbuilds_on (1.0)Axonal RNA Transport Reconstitutionbuilds_on (1.0)R-Loop Resolution Enhancement Therapybuilds_on (1.0)Low Complexity Domain Cross-Linking Inhibitionbuilds_on (1.0)Stress Granule Phase Separation Modulatorsbuilds_on (0.6)Depended On By
Microbial Metabolite-Mediated α-Synuclein Disaggregationbuilds_on (1.0)Enteric Nervous System Prion-Like Propagation Blockadebuilds_on (1.0)Gut Barrier Permeability-α-Synuclein Axis Modulationbuilds_on (0.8)Smartphone-Detected Motor Variability Correctionbuilds_on (0.6)HSP90-Tau Disaggregation Complex Enhancementbuilds_on (0.6)RNA-Binding Competition Therapy for TDP-43 Cross-Seedingrefines (0.5)🧪 Adjacent Hypotheses10 siblings from the same analysis
Stress Granule Phase Separation Modulators
0.72G3BP1 · neurodegeneration · debated
Axonal RNA Transport Reconstitution
0.70HNRNPA2B1 · neurodegeneration · debated
R-Loop Resolution Enhancement Therapy
0.68SETX · neurodegeneration · debated
Mitochondrial RNA Granule Rescue Pathway
0.66SYNCRIP · neurodegeneration · debated
Nucleolar Stress Response Normalization
0.65NPM1 · neurodegeneration · debated
Cryptic Exon Silencing Restoration
0.53TARDBP · neurodegeneration · debated
Mitochondrial RNA Processing Enhancement
0.00LRPPRC · proposed
RNA Splicing Corrector Compounds
0.00TARDBP · proposed
Cross-Disease RNA Granule Dissolution Therapy
0.00G3BP1 · proposed
Proteostasis Network Activation for RBPs
0.00HSPA1A · proposed
🗣 Debate PerspectivesGap Analysis | 4 rounds | 2026-04-01
🔮 Predictions
🔎 Predictions vs Observations1 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| Modulation of TARDBP will affect the proposed pathway | TARDBP knockdown/overexpression shows measurable effect | — no observation — | pending | 0.68 |
🔮 Falsifiable Predictions (1)
pendingconf 68%
Modulation of TARDBP will affect the proposed pathway
Predicted outcome: TARDBP knockdown/overexpression shows measurable effect
Falsification: No effect observed from TARDBP modulation in relevant models
📖 References (11)
- TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS.Yu CH et al.. Cell (2020)
- Autophagy and ALS: mechanistic insights and therapeutic implications.Chua JP et al.. Autophagy (2022)
- N protein of PEDV plays chess game with host proteins by selective autophagy.Zhai X et al.. Autophagy (2023)
- Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43.Walker AK et al.. Acta neuropathologica (2015)
- Evidence-based consensus guidelines for ALS genetic testing and counseling.Roggenbuck J et al.. Annals of clinical and translational neurology (2023)
- TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal dementia.Marks JD et al.. Science translational medicine (2024)
- TDP-43 Pathology in Alzheimer's Disease.Meneses A et al.. Mol Neurodegener (2021)
- Protein transmission in neurodegenerative disease.Peng C et al.. Nat Rev Neurol (2020)
- Credibility analysis of putative disease-causing genes using bioinformatics.["Abel O" et al.. PloS one (2013)
- Amyotrophic lateral sclerosis.Wijesekera LC et al.. Orphanet journal of rare diseases (2009)
- TDP-43 proteinopathies: a new wave of neurodegenerative diseases.de Boer EMJ et al.. Journal of neurology, neurosurgery, and psychiatry (2020)
Related Entities
▸Metadata
| status | proposed |
| _schema_version | 1 |
| hypothesis_type | None |
📊 Evidence Profile
Foundational
Evidence Balance
+0%
Certainty
100%
Debates
2
Incoming
4083
Outgoing
2237
0 supporting
0 contradicting
2 neutral
🌍 Provenance Graph
8 nodes, 14 edges
derives from (14)
hypothesis-h-eea667a9→analysis-SDA-2026-04-01-gap-v2analysis-SDA-2026-04-01-gap-v2→hypothesis-h-4fabd9cehypothesis-h-4fabd9ce→analysis-SDA-2026-04-01-gap-v2analysis-SDA-2026-04-01-gap-v2→hypothesis-h-97aa8486hypothesis-h-97aa8486→analysis-SDA-2026-04-01-gap-v2
▸ Show 9 more
analysis-SDA-2026-04-01-gap-v2→hypothesis-h-8196b893hypothesis-h-8196b893→analysis-SDA-2026-04-01-gap-v2analysis-SDA-2026-04-01-gap-v2→hypothesis-h-c463d225hypothesis-h-c463d225→analysis-SDA-2026-04-01-gap-v2analysis-SDA-2026-04-01-gap-v2→hypothesis-h-1e2bd420hypothesis-h-1e2bd420→analysis-SDA-2026-04-01-gap-v2analysis-SDA-2026-04-01-gap-v2→hypothesis-h-eea667a9analysis-SDA-2026-04-01-gap-v2→hypothesis-h-ecacd219hypothesis-h-ecacd219→analysis-SDA-2026-04-01-gap-v2
🗣 Debate History2 sessions
gap_analysisWhat are the mechanisms underlying rna binding protein dysregulation across als ftd and ad?r4q=0.922026-04-01
gap_analysisWhat are the mechanisms underlying rna binding protein dysregulation across als ftd and ad?r4q=0.922026-04-01+0.000
This artifact has no version history yet.
Linked Artifacts (6308)
🧬 Related Hypotheses — same target / disease (20)
TDP-43 RNA-proteostasis failure across ALS, FTD, and AD/LATE
Score: 0.828 · Target: TARDBP · multi
STMN2 Cryptic Exon Inclusion is the Earliest Loss-of-Function Marker of TDP-43 Nuclear Dep
Score: 0.760 · Target: TARDBP · als
Glial Neuroinflammatory Amplification by TDP-43 Pathology
Score: 0.680 · Target: TARDBP · neurodegeneration
TDP-43 Liquid-Liquid Phase Separation Dominance in Stress Granules Predisposes to Patholog
Score: 0.650 · Target: TARDBP · alzheimers
Glycine-Rich Domain Competitive Inhibition
Score: 0.640 · Target: TARDBP · neurodegeneration
Synaptic RNA Metabolism Dysregulation
Score: 0.620 · Target: TARDBP · neurodegeneration
Cytosolic TDP-43 aggregation sequesters SNAP29 and syntaxin-17, blocking autophagosome-lys
Score: 0.600 · Target: TARDBP · neurodegeneration
TDP-43 LLPS and proteostasis dysregulation in ALS/FTD
Score: 0.600 · Target: TARDBP · neurodegeneration
Small-Molecule Modulation of TDP-43 Liquid-Liquid Phase Separation for ALS/FTD
Score: 0.565 · Target: TARDBP · neurodegeneration
TDP-43 Co-pathology Subtype Identified Through Motor Neuron Transcriptomics
Score: 0.564 · Target: TARDBP · neurodegeneration
Cryptic Exon Silencing Restoration
Score: 0.531 · Target: TARDBP · neurodegeneration
Rational design of small molecules targeting TDP-43 liquid-to-solid phase transition for A
Score: 0.510 · Target: TARDBP · neurodegeneration
G3BP1-TDP-43 Cross-Seeding Drives Co-Aggregation That Prion-Spreads Across Neural Circuits
Score: 0.490 · Target: TARDBP · neurodegeneration
RNA-Binding Competition Therapy for TDP-43 Cross-Seeding
Score: 0.465 · Target: TARDBP · neurodegeneration
RNA Granule Phase Separation as Transient Cross-Seeding Hub
Score: 0.455 · Target: TARDBP · neurodegeneration
C-Terminal Frameshift Protection via RNA-Guided Editing
Score: 0.000 · Target: TARDBP · —
Phase Transition Kinetics Modulators
Score: 0.000 · Target: TARDBP · —
Bi-functional Nuclear Trafficking-Phase Separation Modulators
Score: 0.000 · Target: TARDBP · —
Nuclear Import Receptor Enhancers
Score: 0.000 · Target: TARDBP · —
Prion-Like Domain Stabilizers via Aromatic Interaction Modulators
Score: 0.000 · Target: TARDBP · —
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