DNA Damage Repair Mechanisms Across Neurodegenerative Diseases

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DNA Damage Repair Mechanisms Across Neurodegenerative Diseases

Introduction

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)](/mechanisms/dna-repair-neurodegeneration), [Nucleotide Excision Repair (NER)](/mechanisms/dna-repair-neurodegeneration), [Mismatch Repair (MMR)](/mechanisms/dna-repair-neurodegeneration), and [double-strand break repair](/mechanisms/dna-repair-neurodegeneration) pathways are differentially affected across [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), [Amyotrophic Lateral Sclerosis (ALS)](/diseases/amyotrophic-lateral-sclerosis), [Frontotemporal Dementia (FTD)](/diseases/frontotemporal-dementia), and [Huntington's Disease](/diseases/huntingtons). [@AD_DNA_review]

Disease Comparison Matrix

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DNA Damage Repair Mechanisms Across Neurodegenerative Diseases

Introduction

Disease Comparison Matrix

| 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 |

Base Excision Repair (BER)

Alzheimer's Disease

BER is the most severely impaired pathway in Alzheimer's disease, with documented decreases in [OGG1](/genes/ogg1) activity and [Pol β](/genes/pold1) expression. The accumulation of 8-oxoguanine lesions in nuclear and mitochondrial DNA is a hallmark finding. [@AD_DNA_review]

Key defects: OGG1 glycosylase activity reduced 40-60%
Pol β expression decreased in affected brain regions
XRCC1 ligase activity impaired
Therapeutic target: PARP inhibitors under investigation

Parkinson's Disease

BER impairment in PD is primarily mitochondrial, with [mtDNA deletions](/mechanisms/mtdna-mutations-neurodegeneration) accumulating in [substantia nigra](/brain-regions/substantia-nigra) neurons. The [PINK1](/genes/pink1)-[PARK7](/genes/park7) pathway participates in mitochondrial DNA quality control. [@PD_DNA_review]

Key defects: mtDNA deletions accumulate
Complex I deficiency increases oxidative stress
NRF1 and TFAM regulation altered
Therapeutic target: NAD+ precursors, antioxidants

ALS

BER impairment in ALS relates to oxidative stress from [SOD1](/genes/sod1) mutations and [C9orf72](/genes/c9orf72) hexanucleotide repeat expansions. RNA foci may interfere with DNA repair machinery. [@ALS_DNA_pathology]

Key defects: Increased 8-oxoguanine
SOD1 mutations cause oxidative stress
C9orf72 RNA foci potential interference
Therapeutic target: PARP inhibitors in trials

FTD

FTD shows impaired BER associated with [TDP-43](/genes/tardbp) pathology (in most cases) and [FUS](/genes/fus) pathology (rare cases). The [C9orf72](/genes/c9orf72) repeat expansion causes both ALS-FTD. [@FTD_DNA_repair]

Key defects: TDP-43 affects repair gene expression
C9orf72 repeat carriers show increased damage
Therapeutic target: Under investigation

Huntington's Disease

BER plays a complex role in HD, with [OGG1](/genes/ogg1) actually promoting somatic [CAG repeat expansion](/mechanisms/huntingtons-somatic-cag-expansion-and-dna-repair), while other BER components are protective. [@HD_DNA_modifiers]

Key finding: OGG1 knockout reduces expansion
MSH3 is a major disease modifier
FAN1 nuclease pathway involved
Therapeutic target: MSH3 modulation under study

Nucleotide Excision Repair (NER)

Alzheimer's Disease

NER capacity declines in AD with reduced [XPA](/genes/xpa) and [XPC](/genes/xpc) levels. Chromatin remodeling defects impair repair access to damaged DNA. [@AD_DNA_review]

Key defects: XPA, XPC protein reduced
TFIIH complex altered
Global genome NER (GG-NER) impaired
Therapeutic target: Chromatin modifiers

Parkinson's Disease

NER in PD shows variable decline depending on disease stage and [LRRK2](/genes/lrrk2) genotype. Mitochondrial NER (mitNER) is particularly affected. [@PD_DNA_review]

Variable decline across studies
LRRK2 kinase affects DNA response
Mitochondrial NER impaired
Therapeutic target: LRRK2 inhibitors

ALS/FTD

NER impairment in ALS/FTD involves [CSA (ERCC8)](/genes/ercc8) and [CSB (ERCC6)](/genes/ercc6) pathways, with [TDP-43](/genes/tardbp) pathology affecting expression of repair genes. [@ALS_DNA_pathology]

CSA/CSB pathway involvement
TDP-43 affects transcription
Therapeutic target: None established

Huntington's Disease

NER is not prominently affected in HD compared to other repair pathways.

Double-Strand Break (DSB) Repair

Homologous Recombination (HR)

Mermaid diagram (expand to render)

Disease-Specific Findings

| Disease | Key Proteins | Effect |
|---------|-------------|--------|
| AD | [ATM](/genes/atm) signaling altered | Checkpoint dysfunction |
| PD | [ATR](/genes/atr)-MLK1 axis | Replication stress response |
| ALS | [FUS](/genes/fus) | RNA-DNA damage sensing |
| FTD | [TBK1](/genes/tbk1) | Autophagy-DNA repair link |
| HD | [FAN1](/genes/fan1), RRM2B | Modifier genes identified |

Non-Homologous End Joining (NHEJ)

NHEJ is the predominant DSB repair pathway in neurons. [Ku70](/genes/xrcc6)-[Ku80](/genes/xrcc5) and [DNA-PKcs](/genes/prkdc) form the core machinery. [@ATM_signaling]

AD: Ku70/80 expression altered
PD: DNA-PKcs activity declined
ALS: Functionally impaired
HD: Not prominently affected

ATM/ATR Signaling

The [ATM](/genes/atm)-[ATR](/genes/atr) axis is central to DNA damage response. [ATM](/genes/atm) primarily responds to DSBs while [ATR](/genes/atr) responds to replication stress. Both kinases are dysregulated across neurodegenerative diseases. [@ATM_signaling]

Mismatch Repair (MMR)

MMR is particularly important in [Huntington's Disease](/diseases/huntingtons), where [MSH3](/genes/msh3) is a major modifier locus affecting [somatic CAG expansion](/mechanisms/huntingtons-somatic-cag-expansion-and-dna-repair). The MSH3 knockout delays disease onset in mouse models. [@HD_DNA_modifiers]

| 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 |

Therapeutic Targets

Shared Across Diseases

| 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) |

Disease-Specific Approaches

Alzheimer's: PARP inhibitors, chromatin modifiers, antioxidant therapy

Parkinson's: NAD+ precursors, LRRK2 inhibitors, mitochondrial protectors

ALS: PARP inhibitors, antioxidant therapy, FUS-targeted approaches

FTD: TDP-43 targeted approaches, C9orf72-targeted approaches

Huntington's: MSH3 inhibition, FAN1 modulation, somatic expansion blockers

Clinical Trials

Active and Recruiting Trials

| 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 |

Completed Trials and Key Findings

| 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 |

Key Findings from Major Trials

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).

Emerging Therapeutic Approaches

Somatic expansion blockers: Novel drugs targeting MSH3 and FAN1 to block CAG repeat expansion in HD
NAD+-boosting therapies: Multiple approaches including NR, NMN, and direct PARP inhibitors to enhance DNA repair
Gene therapy for DNA repair genes: Delivery of OGG1, Polβ, or other DNA repair enzymes
Combination approaches: NAD+ precursors + PARP inhibitors for synergistic DNA repair enhancement

Cross-Disease Summary

Mermaid diagram (expand to render)

[DNA Repair Mechanisms in Neurodegeneration](/mechanisms/dna-repair-neurodegeneration)
[DNA Damage Response in Alzheimer's](/mechanisms/dna-damage-response-alzheimers)
[DNA Damage Response in Parkinson's](/mechanisms/dna-damage-response-parkinsons)
[DNA Damage Response in neurons](/mechanisms/dna-damage-response-neurons)
[Somatic CAG Expansion in Huntington's](/mechanisms/huntingtons-somatic-cag-expansion-and-dna-repair)
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)
[Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
[Frontotemporal Dementia](/diseases/frontotemporal-dementia)
[Huntington's Disease](/diseases/huntingtons)

Key Genes

[ATM](/genes/atm) — Ataxia-telangiectasia mutated kinase
[ATR](/genes/atr) — ATM and Rad3-related kinase
[OGG1](/genes/ogg1) — 8-oxoguanine glycosylase
[PARP1](/genes/parp1) — Poly(ADP-ribose) polymerase 1
[XRCC1](/genes/xrcc1) — X-ray repair cross-complementing 1
[XPA](/genes/xpa) — DNA repair protein XPA
[MSH3](/genes/msh3) — MutS homolog 3
[FAN1](/genes/fan1) — FANCD2 Fanconi anemia
[PINK1](/genes/pink1) — PTEN-induced kinase 1
[LRRK2](/genes/lrrk2) — Leucine-rich repeat kinase 2

References

[Thadathil et al., DNA damage and repair in aging and AD (2022)](https://doi.org/10.1016/j.arr.2022.101676). Ageing Research Reviews. 2022.

[Ito et al., DNA damage and repair in Parkinson's disease (2023)](https://doi.org/10.1007/s00702-023-02644-3). Journal of Neural Transmission. 2023.

[DNA repair and somatic expansion in Huntington's disease (2023)](https://doi.org/10.1038/s41582-023-00763-9). Nature Reviews Neurology. 2023.

[DNA damage response in ALS (2023)](https://doi.org/10.1093/brain/awad092). Brain. 2023.

[Impaired DNA repair in FTD (2023)](https://doi.org/10.1186/s40478-023-01512-1). Acta Neuropathologica Communications. 2023.

[Base excision repair in post-mitotic neurons (2023)](https://doi.org/10.1016/j.dnarep.2023.103468). DNA Repair. 2023.

[ATM kinase and DNA damage response in neurodegeneration (2024)](https://doi.org/10.1038/s41420-024-01818-0). Cell Death Discovery. 2024.

Pathway Diagram

The following diagram shows the key molecular relationships involving DNA Damage Repair Mechanisms Across Neurodegenerative Diseases discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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DNA Damage Repair Mechanisms Across Neurodegenerative Diseases

DNA Damage Repair Mechanisms Across Neurodegenerative Diseases

Introduction

Disease Comparison Matrix

DNA Damage Repair Mechanisms Across Neurodegenerative Diseases

Introduction

Disease Comparison Matrix

Base Excision Repair (BER)

Alzheimer's Disease

Parkinson's Disease

ALS

FTD

Huntington's Disease

Nucleotide Excision Repair (NER)

Alzheimer's Disease

Parkinson's Disease

ALS/FTD

Huntington's Disease

Double-Strand Break (DSB) Repair

Homologous Recombination (HR)

Disease-Specific Findings

Non-Homologous End Joining (NHEJ)

ATM/ATR Signaling

Mismatch Repair (MMR)

Therapeutic Targets

Shared Across Diseases

Disease-Specific Approaches

Clinical Trials

Active and Recruiting Trials

Completed Trials and Key Findings

Key Findings from Major Trials

Emerging Therapeutic Approaches

Cross-Disease Summary

Related Pages

Key Genes

References

Pathway Diagram