DNA repair mechanisms are fundamentally important for neuronal survival due to neurons being post-mitotic cells that cannot dilute DNA damage through cell division. Each neurodegenerative disease exhibits distinct patterns of DNA repair pathway impairment, reflecting disease-specific pathology and genetic risk factors. This comparison examines how Base Excision Repair (BER), Nucleotide Excision Repair (NER), Mismatch Repair (MMR), and double-strand break repair pathways are differentially affected across Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and Huntington's Disease. [1]
| Pathway | Alzheimer's Disease | Parkinson's Disease | ALS | FTD | Huntington's Disease |
|---|---|---|---|---|---|
| BER | Severely impaired, OGG1↓ Polβ↓ | Moderate impairment, mtDNA deletions | Moderate impairment | Impaired | OGG1 promotes expansion |
| NER | XPA, XPC reduced | Variable decline | Impaired | Reduced CSA/CSB | Not prominently affected |
| MMR | MSH2/6 altered | Not well studied | Not well studied | Not well studied | Major MSH3 modifier |
| DSBR (HR) | ATM signaling altered | ATR/MLK1 axis | FUS involvement | TBK1 involvement | FAN1, RRM2B modifiers |
| DSBR (NHEJ) | Ku70/80 altered | DNA-PKcs declined | Functionally impaired | Reduced Ku80 | Not prominently affected |
BER is the most severely impaired pathway in Alzheimer's disease, with documented decreases in OGG1 activity and Pol β expression. The accumulation of 8-oxoguanine lesions in nuclear and mitochondrial DNA is a hallmark finding. [1:1]
BER impairment in PD is primarily mitochondrial, with mtDNA deletions accumulating in substantia nigra neurons. The PINK1-PARK7 pathway participates in mitochondrial DNA quality control. [2]
BER impairment in ALS relates to oxidative stress from SOD1 mutations and C9orf72 hexanucleotide repeat expansions. RNA foci may interfere with DNA repair machinery. [3]
FTD shows impaired BER associated with TDP-43 pathology (in most cases) and FUS pathology (rare cases). The C9orf72 repeat expansion causes both ALS-FTD. [4]
BER plays a complex role in HD, with OGG1 actually promoting somatic CAG repeat expansion, while other BER components are protective. [5]
NER capacity declines in AD with reduced XPA and XPC levels. Chromatin remodeling defects impair repair access to damaged DNA. [1:2]
NER in PD shows variable decline depending on disease stage and LRRK2 genotype. Mitochondrial NER (mitNER) is particularly affected. [2:1]
NER impairment in ALS/FTD involves CSA (ERCC8) and CSB (ERCC6 pathways, with TDP-43 pathology affecting expression of repair genes. [3:1]
NER is not prominently affected in HD compared to other repair pathways.
| Disease | Key Proteins | Effect |
|---|---|---|
| AD | ATM signaling altered | Checkpoint dysfunction |
| PD | ATR-MLK1 axis | Replication stress response |
| ALS | FUS | RNA-DNA damage sensing |
| FTD | TBK1 | Autophagy-DNA repair link |
| HD | FAN1, RRM2B | Modifier genes identified |
NHEJ is the predominant DSB repair pathway in neurons. Ku70/Ku80 and DNA-PKcs form the core machinery. [6]
The ATM-ATR axis is central to DNA damage response. ATM primarily responds to DSBs while ATR responds to replication stress. Both kinases are dysregulated across neurodegenerative diseases. [6:1]
MMR is particularly important in Huntington's Disease, where MSH3 is a major modifier locus affecting somatic CAG expansion. The MSH3 knockout delays disease onset in mouse models. [5:1]
| Disease | MSH Status | Therapeutic Implication |
|---|---|---|
| AD | MSH2/6 altered | Not a primary modifier |
| PD | Not well studied | - |
| ALS | Not well studied | - |
| FTD | Not well studied | - |
| HD | MSH3 major modifier | MSH3 inhibition |
| Target | Strategy | Disease Relevance |
|---|---|---|
| PARP | Inhibitors | AD, PD, ALS |
| NAD+ precursors | NMN, NR | AD, PD, ALS |
| ATM/ATR | Kinase modulators | Research phase |
| OGG1 | Activity modulators | AD (↑), HD (↓ to block expansion) |
| NCT ID | Drug/Intervention | Target | Disease | Phase | Status |
|---|---|---|---|---|---|
| NCT03062418 | Nicotinamide riboside (NAD+ precursor) | DNA repair, NAD+ | AD | Phase 2 | Completed |
| NCT03816316 | NR (NAD+ precursor) | Mitochondrial function | PD | Phase 1 | Completed |
| NCT04408638 | PARP inhibitor | DNA repair | ALS | Phase 2 | Completed |
| NCT04348006 | Edaravone | Oxidative stress/DNA | ALS | Phase 3 | Completed |
| NCT05306348 | mTOR inhibitor | Autophagy/DNA repair | Neurodegeneration | Phase 2 | Recruiting |
| NCT05462145 | Autophagy inducer | Protein clearance/DNA | AD/PD | Phase 2 | Recruiting |
| NCT04615923 | Rapamycin | Autophagy/DNA repair | AD/PD | Phase 2 | Active |
| Trial | Compound | Key Findings |
|---|---|---|
| NCT03062418 | Nicotinamide riboside | Showed increased NAD+ levels in CSF; cognitive outcomes mixed |
| NCT03816316 | NR | Safe and well-tolerated; showed biomarker changes |
| NCT04408638 | Eribulin | PARP inhibition showed target engagement in ALS |
| NCT04348006 | Edaravone | Approved for ALS; reduces oxidative stress and DNA damage |
NAD+ Precursors: Nicotinamide riboside (NR) tested in AD (NCT03062418) and PD (NCT03816316) showed increased NAD+ levels in CSF and peripheral tissues. Cognitive benefits were modest but biomarker effects were promising.
PARP Inhibition: Multiple trials tested PARP inhibitors for neuroprotection. Eribulin (NCT04408638) showed target engagement in ALS. PARP inhibition protects against excitotoxicity and oxidative DNA damage.
Oxidative Stress: Edaravone (NCT04348006) approved for ALS reduces oxidative stress and may protect against DNA damage. Demonstrated survival benefit in Phase 3.
Autophagy Enhancement: mTOR inhibitors enhance autophagy which may help clear damaged DNA and improve DNA repair efficiency (NCT04615923, NCT05306348).
DNA damage and repair in aging and Alzheimer's disease. Ageing Research Reviews. 2024. ↩︎ ↩︎ ↩︎
DNA damage and repair in Parkinson's disease. Journal of Neural Transmission. 2024. ↩︎ ↩︎
DNA damage response in amyotrophic lateral sclerosis. Brain. 2025. ↩︎ ↩︎
Impaired DNA repair in frontotemporal dementia. Acta Neuropathologica. 2024. ↩︎
DNA repair modifiers in Huntington's disease. Nature Reviews Neurology. 2024. ↩︎ ↩︎
ATM kinase and DNA damage response in neurodegeneration. Cell Death Discovery. 2025. ↩︎ ↩︎