Parthanatos (from Greek thanatos, meaning death) is a form of programmed cell death that is morphologically and mechanistically distinct from apoptosis, necrosis, or other known cell death pathways PMID: 41699331. The term was coined to describe a caspase-independent, PAR polymer (PAR)-dependent cell death mechanism that involves the mitochondrial translocation of apoptosis-inducing factor (AIF)[@hardie2005] PMID: 32381174. This cell death pathway has emerged as a critical mechanism in various neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), as well as in acute neurological insults such as stroke and traumatic brain injury[@yu2006] PMID: 33540042.
```mermaid
flowchart TD
subgraph TRIGGERS["Pathological Triggers"]
A1["DNA Damage<br/>(Oxidative Stress)"]
A2["Excitotoxicity<br/>(Glutamate)"]
A3["Mitochondrial Toxins<br/>(MPTP/MPP+, Rotenone)"]
A4["Protein Aggregates<br/>(Abeta, alpha-Syn, Htt)"]
A5["Ischemia/Reperfusion"]
end
subgraph PARP_ACTIVATION["PARP1 Overactivation"]
B1["PARP1 Binds DNA Breaks"]
B2["Excessive PAR Synthesis"]
B3["NAD+ Depletion"]
B4["ATP Depletion"]
end
Parthanatos (from Greek thanatos, meaning death) is a form of programmed cell death that is morphologically and mechanistically distinct from apoptosis, necrosis, or other known cell death pathways PMID: 41699331. The term was coined to describe a caspase-independent, PAR polymer (PAR)-dependent cell death mechanism that involves the mitochondrial translocation of apoptosis-inducing factor (AIF)[@hardie2005] PMID: 32381174. This cell death pathway has emerged as a critical mechanism in various neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), as well as in acute neurological insults such as stroke and traumatic brain injury[@yu2006] PMID: 33540042.
Unlike apoptosis, which is an orderly, energy-dependent process involving caspase activation and cellular dismantling, parthanatos represents a catastrophic metabolic failure characterized by rapid NAD+ depletion, AIF-mediated DNA fragmentation, and cellular disintegration. Understanding this pathway provides insights into neurodegeneration mechanisms and identifies potential therapeutic targets for neuroprotective strategies.
The concept of parthanatos emerged from studies on the role of poly(ADP-ribose) polymerase (PARP) in cell death. In the early 2000s, researchers observed that overactivation of PARP1 following severe DNA damage led to a distinctive form of cell death that did not depend on caspase activation[@chiarugi2002]. Dr. Graham Hardie's group at the University of Dundee characterized this pathway and proposed the term "parthanatos" to distinguish it from other forms of programmed cell death.
Key historical milestones include:
Poly(ADP-ribose) polymerase 1 (PARP1) is a nuclear enzyme that catalyzes the addition of ADP-ribose polymers to various proteins in response to DNA damage. Under physiological conditions, PARP1 activation is protective, facilitating DNA repair through:
Apoptosis-inducing factor (AIF) is a flavoprotein normally located in the mitochondrial intermembrane space. In parthanatos, AIF undergoes a dramatic transformation:
The parthanatos pathway creates a catastrophic energy crisis:
This creates a feed-forward loop where energy depletion further impairs DNA repair, exacerbating DNA damage and PARP activation.
Endonuclease G (EndoG) is a mitochondrial nuclease that translocates to the nucleus alongside AIF during parthanatos. EndoG contributes to DNA fragmentation and is responsible for the characteristic large-scale DNA cleavage observed in parthanatos[@zhivotovsky2003].
Parthanatos has emerged as a significant cell death pathway in PD:
Multiple mechanisms in AD lead to parthanatos activation:
Parthanatos is implicated in motor neuron death in ALS:
The parthanatos pathway contributes to striatal neuron death in HD:
Parthanatos is a major cell death mechanism in acute brain injury:
Several PARP inhibitors have been developed for neuroprotection:
Since parthanatos depletes NAD+, restoration strategies are neuroprotective:
Targeting AIF translocation is a potential strategy:
EndoG inhibitors could prevent DNA fragmentation in parthanatos:
Detecting parthanatos in patients is challenging but important:
PARP inhibitors have advanced to clinical trials for neurodegenerative applications:
| Agent | Condition | Phase | NCT ID | Status |
|-------|-----------|-------|--------|--------|
| Veliparib (ABT-888) | Parkinson's disease | Phase II | NCT03996226 | Recruiting |
| Olaparib | Neuroprotection post-stroke | Phase II | NCT01876303 | Completed |
| Rucaparib | ALS | Phase I | NCT05152459 | Recruiting |
| INO-1001 | Cardiac surgery neuroprotection | Phase I | NCT00217356 | Completed |
| PJ34 (experimental) | Ischemic stroke | Preclinical | N/A | Active |
PARP inhibitor trials in neurodegeneration: The veliparib Phase II trial (NCT03996226) tests whether PARP inhibition slows PD progression by protecting dopaminergic neurons from PAR-mediated cell death. Rucaparib is being evaluated in ALS (NCT05152459) given the documented PARP activation in motor neuron models[@mcgough2020].
Stroke and neuroprotection: Olaparib and INO-1001 were tested for neuroprotection in stroke and cardiac surgery contexts, establishing safety profiles for brain-penetrant PARP inhibitors[@liu2021]. These trials inform dosing and safety parameters relevant to chronic neurodegenerative applications.
Combination approaches: PARP inhibitors are being combined with NAD+ precursors in early-phase trials, based on the mechanistic rationale that restoring NAD+ while blocking PARP hyperactivation provides synergistic neuroprotection.
Pipeline: Second-generation PARP inhibitors with improved brain penetration are in early development for neurodegenerative indications.
The biomarkers described above have clinical utility for patient stratification and target engagement:
PARP inhibitors represent disease-modifying potential across AD, PD, and ALS by interrupting a core cell death pathway:
Poly(ADP-ribose) (PAR) is a unique biopolymer synthesized by poly(ADP-ribose) polymerase (PARP) enzymes in response to cellular stress and DNA damage. This polymer plays critical roles in maintaining genomic integrity and cellular homeostasis, while dysregulated PAR metabolism has been increasingly recognized as a contributor to neurodegenerative disease pathogenesis.
PARylation is the enzymatic process by which PAR polymers are synthesized. The reaction begins when PARP enzymes, particularly PARP1 and PARP2, detect DNA strand breaks through their DNA-binding domains [@schreiber2006]. Upon binding to damaged DNA, PARP catalytic activity becomes dramatically activated, leading to the transfer of ADP-ribose units from nicotinamide adenine dinucleotide (NAD+) onto specific amino acid residues of target proteins, as well as onto the growing PAR chain itself [@gibson2022].
The PARylation reaction proceeds through three main steps: first, PARP enzymes hydrolyze NAD+ to release nicotinamide and then transfer the ADP-ribose moiety to target proteins, forming an ester bond between the ADP-ribose and glutamate, aspartate, or lysine residues. Second, the initial mono-ADP-ribosylated protein can serve as a primer for chain elongation, with additional ADP-ribose units added in linear or branched configurations. Third, the polymer can be released from the target protein or remain covalently attached, functioning as a post-translational modification [@luo2012].
PAR is composed of repeating ADP-ribose units linked by ribose-ribose glycosidic bonds. Each ADP-ribose unit consists of adenosine diphosphate linked to a ribose sugar, with the polymer forming through 2′-5′ phosphodiester bonds between ribose moieties [@rosenthal2019].
The structure of PAR exhibits remarkable complexity. Linear chains can extend from 2 to 200 or more ADP-ribose units, with average chain lengths typically ranging between 20-50 units under physiological conditions. Importantly, PAR polymers contain branching points, typically occurring every 20-50 linear subunits, creating a branched, tree-like architecture [@alemasova2019]. This branching structure is generated when PARP enzymes add ADP-ribose units to the 2′-hydroxyl position of the growing chain rather than the terminal position, creating the characteristic branched morphology.
The structural heterogeneity of PAR allows for diverse binding interactions with effector proteins and influences cellular signaling outcomes. Different polymer lengths and branching patterns have been associated with distinct biological functions, suggesting that PAR structure serves as a molecular code for specific cellular responses [@teloni2016].
PAR participates in numerous cellular processes essential for maintaining cellular function and survival. In the DNA damage response, PARylation facilitates recruitment of DNA repair proteins to sites of damage, acting as a molecular beacon that coordinates the sequential assembly of repair machinery [@wu2023]. The negatively charged PAR polymer also promotes chromatin relaxation by evicting histones and other chromatin-associated proteins, thereby increasing accessibility of DNA repair factors to damaged sites.
Beyond DNA repair, PAR regulates transcription factor activity, influences telomere maintenance, and modulates cellular stress responses. During severe genotoxic stress, PARP enzymes contribute to metabolic regulation by consuming NAD+ and modulating energy homeostasis [@bai2019]. Additionally, PARylated proteins can form signaling complexes that regulate inflammation and immune responses.
Timely degradation of PAR is essential for cellular homeostasis, and this function is primarily performed by poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribosylhydrolase 3 (ARH3) [@gagn2018]. PARG exhibits exo-glycosidase activity, progressively removing ADP-ribose units from the polymer chain terminus, while also possessing endo-glycosidase activity that can cleave within branched regions of the polymer.
ARH3 complements PARG function by specifically hydrolyzing the ester bond between ADP-ribose and target proteins, completing the cycle of PAR metabolism [@mashimo2021]. The coordinated activity of these enzymes ensures that PAR signals are transient and appropriately regulated, preventing accumulation of toxic polymer species.
Dysregulated PAR metabolism has emerged as a significant contributor to neurodegeneration. Excessive PARP activation following stroke, traumatic brain injury, or neurodegenerative disease triggers NAD+ depletion, leading to cellular energy crisis and ultimately cell death [@andrabi2023]. Furthermore, PAR polymers can directly promote neurotoxicity by facilitating the release of apoptosis-inducing factor (AIF) from mitochondria, triggering caspase-independent cell death pathways.
In Alzheimer's disease, Parkinson's disease, and related disorders, altered PAR metabolism has been observed in patient tissue and model systems, with evidence suggesting that chronic low-level PARP activation may contribute to progressive neuronal dysfunction [@strosznajder2020]. These findings have generated interest in developing PARP inhibitors as neuroprotective therapeutic agents.
The poly(ADP-ribose) polymerase (PARP) family represents a group of enzymes crucial for cellular homeostasis, DNA repair, and stress responses. In mammals, this family comprises 17 members, with PARP1, PARP2, PARP3, and the tankyrases (PARP5a and PARP5b) being the most extensively studied in the context of neurodegeneration [@ame2004].
PARP1 is the founding and most abundant member of the PARP family, accounting for approximately 80-90% of cellular poly(ADP-ribosyl)ation activity [@bai2015]. Structurally, PARP1 contains three main domains: an N-terminal DNA-binding domain that recognizes DNA strand breaks, a central automodification domain, and a C-terminal catalytic domain responsible for NAD⁺ binding and polymer synthesis [@langelier2012].
In response to DNA damage, PARP1 rapidly binds to single-strand and double-strand breaks, undergoing conformational changes that activate its catalytic function. Activated PARP1 synthesizes poly(ADP-ribose) (PAR) chains onto itself and nearby acceptor proteins, creating a scaffold that recruits DNA repair factors including XRCC1, DNA ligase III, and polymerase β [@woodhouse2008].
In neurodegeneration, PARP1 hyperactivation becomes pathological. Excessive DNA damage, as occurs in Alzheimer's disease, Parkinson's disease, and stroke, leads to prolonged PARP1 activation. This depletes cellular NAD⁺ and ATP reserves, ultimately triggering programmed cell death pathways. PAR-mediated cell death (parthanatos) involves mitochondrial release of apoptosis-inducing factor (AIF), which translocates to the nucleus and causes large-scale DNA fragmentation [@david2009].
PARP2 shares structural and functional homology with PARP1 but displays distinct biological roles. While PARP2 can compensate for PARP1 in certain DNA repair pathways, it exhibits unique substrate specificities and activation mechanisms [@schreiber2002].
PARP2 is particularly important for repairing DNA double-strand breaks through homologous recombination and for resolving replication stress. Unlike PARP1, which responds primarily to single-strand breaks, PARP2 demonstrates higher affinity for DNA double-strand breaks and participates in alternative lengthening of telomeres maintenance [@djeungoubogout2015].
In neurodegenerative contexts, PARP2 appears to play both protective and detrimental roles. Genetic deletion of PARP2 in mouse models reduces DNA repair capacity and accelerates neurodegeneration, yet selective PARP2 inhibition may offer therapeutic benefits by preventing excessive PAR synthesis without completely abolishing base excision repair [@shall2000].
PARP3 represents the third catalytically active PARP in mammals. While its roles in neurodegeneration remain less characterized, PARP3 participates in mitotic spindle assembly, centrosome function, and response to genotoxic stress. Recent studies suggest PARP3 may modulate neuroinflammation through regulation of NF-κB signaling pathways [@loseva2017].
Other PARP family members, including PARP4 (vPARP), PARP6, PARP7, PARP8, PARP9-12, and PARP14-16, primarily function in cellular signaling, stress responses, and immune regulation rather than classical DNA repair. Their contributions to neurodegeneration are still being elucidated but represent an emerging area of research [@gibson2012].
Tankyrases (PARP5a/TNKS1 and PARP5b/TNKS2) possess unique functions in Wnt signaling, telomerase regulation, and microtubule dynamics. Unlike PARP1 and PARP2, tankyrases primarily catalyze mono(ADP-ribosyl)ation rather than poly(ADP-ribosyl)ation [@hsiao2008].
In neurodegeneration, tankyrases contribute to pathological protein aggregation. In Alzheimer's disease, tankyrase-mediated ADP-ribosylation promotes tau hyperphosphorylation and filament formation. Tankyrase inhibition reduces tau pathology in mouse models, highlighting therapeutic potential [@zhang2014].
Tankyrase inhibitors have also shown promise in Parkinson's disease models by stabilizing axonal integrity and reducing α-synuclein toxicity. However, the broad cellular functions of tankyrases raise concerns regarding mechanism-based toxicity [@okamoto2018].
PARP inhibitors represent a promising therapeutic strategy for neurodegenerative diseases. First-generation inhibitors (olaparib, rucaparib, niraparib) are FDA-approved for oncology but show limited brain penetration.
Second-generation inhibitors with improved CNS penetration are under development. Novel compounds target PARP1/2 for neuroprotection while sparing tankyrases to avoid unwanted effects on Wnt signaling. Repositories of small-molecule PARP inhibitors demonstrate efficacy in animal models of stroke, traumatic brain injury, and Alzheimer's disease [@wahlberg2012].
Clinical trials evaluating PARP inhibitors in neurodegenerative conditions remain limited. Challenges include selecting appropriate patient populations, determining optimal treatment windows, and managing potential adverse effects from chronic PARP inhibition. Biomarker-driven approaches measuring PAR levels or DNA damage markers may aid in patient selection [@fouquerel2021].
Parthanatos represents a unique form of programmed cell death that is distinct from apoptosis and necrosis, characterized by its dependence on poly(ADP-ribose) polymerase (PARP) activation and the subsequent translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus. Understanding the mitochondrial mechanisms underlying parthanatos provides critical insights into neurodegenerative processes in stroke, Parkinson's disease, and Alzheimer's disease.
Mitochondria serve as the cellular powerhouses, generating ATP through oxidative phosphorylation in the inner mitochondrial membrane. Beyond energy production, these organelles play critical roles in regulating reactive oxygen species (ROS), maintaining calcium homeostasis, and initiating cell death pathways. Under physiological conditions, mitochondria convert nutrients into ATP through the electron transport chain, a process that inevitably produces ROS as a byproduct. However, antioxidant systems including superoxide dismutase, glutathione peroxidase, and peroxiredoxins neutralize excess ROS, maintaining redox balance and preventing oxidative damage to cellular components. This delicate equilibrium is essential for neuronal survival, given the high metabolic demands and oxidative vulnerability of neural tissue.
Excessive DNA damage triggers robust PARP activation, which consumes NAD+ as a substrate for poly(ADP-ribose) synthesis. This depletes cellular NAD+ pools, severely compromising mitochondrial function [@andrabi2010]. NAD+ serves as an essential cofactor in mitochondrial respiration, and its depletion disrupts oxidative phosphorylation, leading to rapid ATP exhaustion. Furthermore, PARP activation causes parthanatos-specific alterations in mitochondrial calcium handling, making neurons more susceptible to calcium-induced mitochondrial dysfunction. The resulting bioenergetic crisis creates a self-amplifying cycle where impaired ATP production further compromises cellular repair mechanisms and ion pump function.
The release of AIF from mitochondria represents a hallmark event in parthanatos. Unlike apoptosis where cytochrome c release is caspase-dependent, AIF translocation occurs through a caspase-independent pathway triggered by PAR accumulation in the cytosol. Research demonstrates that PAR polymers generated during excessive PARP activation bind to AIF, promoting its release from the mitochondrial intermembrane space [@wang2011]. This translocation is facilitated by the mitochondrial permeability transition pore, which opens in response to calcium overload and oxidative stress. Once in the cytosol, AIF translocates to the nucleus, where it recruits endonucleases including MIF, causing massive DNA fragmentation and chromatin condensation characteristic of parthanatos.
The mitochondrial permeability transition pore (mPTP) serves as a critical mediator in parthanatos execution [@basso2005]. This nonselective channel spans the inner mitochondrial membrane, and its opening causes collapse of the mitochondrial membrane potential, swelling of the mitochondrial matrix, and rupture of the outer membrane. In parthanatos, mPTP opening is triggered by calcium dysregulation, oxidative stress, and NAD+ depletion. Cyclophilin D, a peptidyl-prolyl isomerase located in the mitochondrial matrix, plays a key regulatory role in pore opening. Pharmacological inhibition of cyclophilin D or genetic deletion of its gene attenuates AIF release and provides neuroprotection in various models of neurodegeneration.
Mitochondrial DNA (mtDNA) damage significantly contributes to parthanatos-associated neurodegeneration [@lin2006]. Unlike nuclear DNA, mtDNA lacks histones and is located in close proximity to the electron transport chain, making it particularly vulnerable to ROS-induced damage. During parthanatos, excessive ROS generation overwhelms mitochondrial repair mechanisms, leading to accumulation of mtDNA lesions. Damaged mtDNA further impairs oxidative phosphorylation, creating a vicious cycle of bioenergetic failure and oxidative stress. Additionally, PARP activation may directly affect mitochondrial base excision repair pathways, compromising the cell's ability to repair mtDNA damage. The progressive accumulation of mtDNA mutations and deletions observed in neurodegenerative diseases likely reflects repeated episodes of parthanatos-like cell death throughout the lifespan.
Parthanatos, a form of regulated necrotic cell death distinct from apoptosis, is fundamentally linked to the cell's DNA damage response (DDR) machinery. Understanding how DNA lesions trigger PARP activation and subsequently lead to cell death provides critical insights into neurodegenerative processes where this cell death pathway plays a prominent role [@dawson2003].
The poly(ADP-ribose) polymerase (PARP) family of enzymes, particularly PARP1, serves as a primary sensor for various forms of DNA damage. Single-strand breaks (SSBs) represent one of the most frequent DNA lesions that activate PARP1. These interruptions in the phosphodiester backbone can arise from spontaneous hydrolysis, oxidative damage, or during normal metabolic processes [@caldecott2008]. When the replication machinery encounters an unrepaired SSB, it can convert these lesions into more dangerous double-strand breaks (DSBs), which pose an even greater threat to genomic integrity.
Oxidative DNA damage constitutes a major trigger for PARP activation in the context of neurodegeneration. Reactive oxygen species (ROS), produced as byproducts of mitochondrial respiration, constantly challenge neuronal DNA. Guanine residues are particularly susceptible to oxidation, forming 8-oxoguanine (8-oxoG), a highly mutagenic lesion that, if not properly repaired, leads to G:C to T:A transversions during replication [@markkanen2013].
Base excision repair (BER) serves as the primary pathway for repairing the types of DNA damage that activate PARP1. This crucial repair mechanism handles small, non-helix-distorting lesions including SSBs, oxidized bases, and alkylation damage [@krokan2013]. The BER cascade is initiated by DNA glycosylases that recognize and flip damaged bases out of the helix, cleaving the glycosidic bond to release the damaged base. AP endonuclease (APE1) then processes the resulting abasic site, creating a single-strand break that is subsequently filled in by DNA polymerase β and sealed by DNA ligase III.
PARP1 participates intimately in this repair process by binding to DNA break sites and undergoing a conformational change that triggers its catalytic activity. Upon activation, PARP1 synthesizes poly(ADP-ribose) (PAR) chains that serve as docking platforms for repair factors, including XRCC1, DNA ligase III, and DNA polymerase β, effectively assembling the BER repair complex at damage sites [@masson1998].
The capacity of PARP1 to sense DNA damage rapidly and orchestrate repair makes it a frontline defender of genomic integrity. PARP1 contains multiple DNA binding domains that allow it to detect both single-strand and double-strand breaks with high sensitivity [@dadda2014]. Upon DNA damage recognition, PARP1 undergoes an allosteric change that dramatically increases its catalytic efficiency, enabling rapid synthesis of PAR polymers at damage sites.
This rapid response serves dual purposes: recruiting DNA repair machinery and alerting neighboring cells through paracrine signaling when damage is extensive. The PAR-dependent recruitment of repair proteins such as XRCC1 and DNA ligase III creates a positive feedback loop that accelerates BER completion under moderate damage conditions.
Under conditions of excessive DNA damage, the protective function of PARP1 can shift catastrophically toward cell death induction. When damage exceeds the capacity of BER, hyperactivated PARP1 consumes massive quantities of its substrate NAD+ in a futile attempt to signal for repair [@andrabi2008]. This NAD+ depletion has two major consequences: first, it impairs cellular energy production by limiting glycolysis and oxidative phosphorylation, and second, it triggers the release of apoptosis-inducing factor (AIF) from mitochondria.
AIF translocates to the nucleus where it mediates large-scale DNA fragmentation through a PAR-dependent, caspase-independent mechanism characteristic of parthanatos. The depletion of cellular ATP combined with AIF-mediated DNA degradation creates a point of no return, committing the cell to death [@yu2006a]. This switch from repair to death represents a critical failsafe mechanism that eliminates cells with potentially dangerous genomic lesions, but in neurons, this protective mechanism becomes pathological when DNA damage accumulates faster than repair can proceed.
Neurons face unique challenges regarding DNA damage accumulation. As post-mitotic cells, they cannot rely on replication-coupled repair pathways and must maintain genomic integrity throughout lifespan. Accumulating evidence links impaired DNA repair with neurodegeneration, particularly in conditions involving oxidative stress [@barzilai2007].
Aging itself is associated with reduced BER efficiency in the brain, with decreased activity of key repair enzymes including OGG1 and APE1. This age-related decline creates a permissive environment for DNA damage accumulation, setting the stage for inappropriate PARP activation and subsequent parthanatos. In diseases including Alzheimer's, Parkinson's, and Huntington's disease, markers of enhanced DNA damage and PARP activation are consistently observed in affected brain regions [@wang2022].
The intersection of biological aging and parthanatos represents a critical nexus in understanding neurodegenerative disease pathogenesis. As neurons accumulate molecular damage across the lifespan, they become increasingly vulnerable to PARP-1-mediated cell death pathways. This section explores how aging-related molecular changes create a permissive environment for parthanatos execution.
During normal aging, cellular NAD+ levels decline steadily in multiple tissues, including the brain. This reduction stems from decreased synthesis, increased consumption by metabolic enzymes, and impaired salvage pathway activity [@imai2014]. Since NAD+ serves as the essential substrate for PARP-1 catalytic activity, age-related NAD+ depletion paradoxically creates a dual problem: insufficient NAD+ limits normal DNA repair functions while simultaneously predisposing neurons to dysregulated PARP activation when DNA damage occurs [@bai2011].
Aged neurons also exhibit elevated basal PARP-1 expression and activity, even without acute DNA damage. This chronic, low-level PARP activation consumes remaining NAD+ pools, creating a vicious cycle where depleted NAD+ impairs mitochondrial function while PARP hyperactivity accelerates energy crisis [@liu2022]. The consequence is neuronal populations operating in a perpetual state of metabolic vulnerability.
Neurons are particularly susceptible to DNA damage accumulation due to their post-mitotic nature and high metabolic demand. With aging, the DNA damage response pathways become progressively compromised [@krishnan2021]. Key repair mechanisms including base excision repair, nucleotide excision repair, and single-strand break repair show reduced efficiency in aged neurons.
This repair deficit creates a scenario where endogenous DNA damage—arising from oxidative metabolism, environmental exposures, and normal cellular processes—fails to be resolved. Persistent DNA damage triggers sustained PARP-1 activation, initiating the parthanatos cascade when repair attempts fail [@fatokun2014]. The aging neuron's diminished capacity to handle DNA insult thus transforms routine metabolic challenges into potential cell death signals.
Aging mitochondria demonstrate multiple structural and functional alterations: accumulated mtDNA mutations, reduced electron transport chain efficiency, increased reactive oxygen species production, and impaired quality control mechanisms [@sun2016]. These changes render aged neurons particularly susceptible to PARP-1-mediated mitochondrial collapse.
When PARP-1 becomes hyperactivated, massive NAD+ depletion occurs in the cytosol. Mitochondria lose access to this critical substrate, compromising ATP production exactly when energy demands increase. PAR polymer accumulation directly disrupts mitochondrial membrane potential and promotes AIF release from the mitochondrial intermembrane space [@yu2002]. Aged neurons, already operating with marginal energy reserves, cannot survive this additional insult.
Chronic low-grade inflammation, termed "inflammaging," characterizes the aging brain microenvironment. Elevated levels of pro-inflammatory cytokines, activated microglia, and circulating damage-associated molecular patterns create conditions favorable to PARP activation [@franceschi2000].
Inflammaging promotes DNA damage through multiple pathways: increased oxidative stress, mitochondrial dysfunction, and direct inflammatory mediator effects on nuclear DNA. Simultaneously, inflammatory signaling can sensitize cells toward cell death pathways. The combination of DNA damage susceptibility and pre-activated death machinery makes aged neurons exceptionally vulnerable to parthanatos when additional stressors arise [@kim2022].
Understanding age-related vulnerabilities opens therapeutic avenues. NAD+ replenishment strategies using precursors such as nicotinamide riboside show promise in preclinical models for restoring neuronal NAD+ pools and improving mitochondrial function [@zhang2016]. Enhancing DNA repair capacity through pharmacological modulation of PARP activity or repair pathway components represents another approach. Senolytic agents targeting chronic inflammatory processes may additionally reduce the inflammaging burden that promotes parthanatos susceptibility.
Combination strategies addressing multiple aging-related vulnerabilities—NAD+ depletion, DNA repair impairment, mitochondrial dysfunction, and neuroinflammation—may prove most effective for preventing parthanatos in aged neurons.