DNA Damage and Repair Mechanisms in Neurodegenerative Disease

Genome stability is critical for the longevity of postmitotic neurons, which are uniquely susceptible to damage from metabolic by-products, environmental stressors and activity-induced DNA breaks. Major lesions include single-strand breaks, oxidative base modifications and double-strand breaks, each countered by dedicated repair pathways such as base excision repair, nucleotide excision repair and double-strand break repair. Neuronal repair capacity declines with age and is further compromised in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and Huntington’s disease, leading to accumulation of DNA lesions, transcriptional dysregulation and cell death. Intriguingly, transient double-strand breaks also serve physiological roles in neural plasticity by enabling rapid gene induction during learning. Disruption of the delicate balance between damage induction and repair underpins genome instability, synaptic dysfunction and cognitive decline in neurodegenerative disorders, highlighting DNA repair as a potential therapeutic target.

Research from Nature Portfolio

Recent studies have identified a specialised repair complex assembled in active neurons around the transcription factor NPAS4 that couples synaptic activity to the repair of double-strand breaks at regulatory elements, partially protecting against age-dependent mutational load. Disruption of this mechanism impairs activity-dependent transcriptional programmes and reduces organismal lifespan. Parallel work has mapped the balance between base excision repair and double-strand break repair across distinct brain regions, revealing that single-strand breaks can reversibly convert to double-strand breaks in response to oxidative state, a dynamic equilibrium that may act as a physiological checkpoint to preserve genomic stability in the long-lived neurons.

DNA Damage and Repair Mechanisms in Neurodegenerative Disease publication trend

The graph below shows the total number of articles in dna damage and repair mechanisms in neurodegenerative disease across all publications each year (not limited to Nature Index journals).

Technical terms

DNA double-strand break: A lesion in which both strands of the DNA helix are severed, requiring coordinated repair to prevent genome instability.

Base excision repair (BER): A pathway that identifies and removes small, non-helix-distorting base lesions, including oxidative and alkylation damage, via specialised glycosylases and endonucleases.

Oxidative stress: The imbalance between production of reactive oxygen species and antioxidant defences, leading to damage of DNA, proteins and lipids.

NPAS4–NuA4 complex: A neuron-specific chromatin-modifying assembly that recruits repair machinery to activity-induced break sites in regulatory DNA elements.

Somatic mutation: A genetic alteration acquired by a cell that can accumulate over time, potentially disrupting neuronal function and contributing to disease.

References

1. A NPAS4–NuA4 complex couples synaptic activity to DNA repair. Nature (2023).
2. Base excision repair and double strand break repair cooperate to modulate the formation of unrepaired double strand breaks in mouse brain. Nature Communications (2024).
3. Redox dysregulation as a driver for DNA damage and its relationship to neurodegenerative diseases. Translational Neurodegeneration (2023).
4. The role of aging and brain‐derived neurotrophic factor signaling in expression of base excision repair genes in the human brain. Aging Cell (2023).
5. The Role of DNA Damage in Neural Plasticity in Physiology and Neurodegeneration. Frontiers in Cellular Neuroscience (2022).