Oxidative DNA Damage in Neurodegenerative Diseases

Oxidative DNA damage arises from an imbalance between reactive oxygen species (ROS) and cellular antioxidant defences, compromising genomic integrity in post‐mitotic neurons. In Alzheimer’s, Parkinson’s and related disorders, mitochondrial dysfunction, amyloid pathology and impaired DNA repair converge to generate single‐ and double‐strand breaks, base lesions and mitochondrial DNA (mtDNA) oxidation. Accumulated lesions disrupt transcription, promote synaptic dysfunction and trigger inflammatory cascades. Deficits in repair pathways—such as base excision repair and double‐strand break resolution—further exacerbate neuronal vulnerability, leading to tau hyperphosphorylation, protein aggregation and cognitive decline. Understanding the mechanisms linking ROS generation, DNA lesion formation and repair capacity is key to identifying biomarkers and designing interventions that bolster genome maintenance and slow neurodegenerative progression.

Research from Nature Portfolio

Recent work in transgenic rat models has demonstrated that intraneuronal amyloid-β accumulation precedes plaque formation, inducing early oxidative stress and DNA double-strand breaks (DSBs) in hippocampal neurons. Upregulation of endonucleases and repair factors accompanies these lesions, alongside changes in synaptic‐plasticity genes that may reflect maladaptive compensatory responses.

Foundational studies have shown that depletion of neuronal BRCA1 in Alzheimer’s models leads to an accumulation of DSBs, synaptic plasticity impairments and learning deficits. Neuronal activity modulates BRCA1 levels, while amyloid-β oligomers promote its degradation, highlighting a link between pathological protein burden, repair factor loss and cognitive decline.

Investigations into mitochondrial transcription factor A (TFAM) in Alzheimer’s mouse models reveal that exogenous TFAM expression reduces mtDNA oxidation, lowers intracellular amyloid-β and restores expression of protective proteins such as transthyretin. These findings suggest that enhancing mtDNA maintenance can break the vicious cycle of mitochondrial ROS production and amyloid accumulation.

Oxidative DNA Damage in Neurodegenerative Diseases publication trend

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

Technical terms

Oxidative stress: Imbalance between production of ROS and antioxidant defence, leading to macromolecular damage.

Reactive oxygen species (ROS): Highly reactive oxygen‐derived molecules that can damage DNA, proteins and lipids.

DNA double-strand break (DSB): A lesion in which both strands of the DNA helix are severed, posing a severe threat to genome stability.

Base excision repair (BER): A pathway that recognises and repairs small, non-helix-distorting base lesions in nuclear and mitochondrial DNA.

Mitochondrial transcription factor A (TFAM): A nuclear‐encoded protein that binds mtDNA, maintains its structure and regulates mitochondrial gene expression.

References

1. Early oxidative stress and DNA damage in Aβ-burdened hippocampal neurons in an Alzheimer’s-like transgenic rat model. Communications Biology (2024).
2. DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice. Nature Communications (2015).
3. Human mitochondrial transcriptional factor A breaks the mitochondria-mediated vicious cycle in Alzheimer’s disease. Scientific Reports (2016).
4. Neuronal double-stranded DNA accumulation induced by DNase II deficiency drives tau phosphorylation and neurodegeneration. Translational Neurodegeneration (2024).
5. Adaptive and Maladaptive DNA Breaks in Neuronal Physiology and Alzheimer’s Disease. International Journal of Molecular Sciences (2024).
6. A neuronal DNA damage response is detected at the earliest stages of Alzheimer's neuropathology and correlates with cognitive impairment in the Medical Research Council's Cognitive Function and Ageing Study ageing brain cohort. Neuropathology and Applied Neurobiology (2015).