DNA damage and repair: relevance to mechanisms of neurodegeneration

Topic: Brain proteins, microglia and lab models

DNA damage is a form of cell stress and injury that has been implicated in the pathogenesis of many neurologic disorders, including amyotrophic lateral sclerosis, Alzheimer disease, Down syndrome, Parkinson disease, cerebral ischemia, and head trauma. However, most data reveal only associations, and the role for DNA damage in direct mechanisms of neurodegeneration is vague with respect to being a definitive upstream cause of neuron cell death, rather than a consequence of the degeneration. Although neurons seem inclined to develop DNA damage during oxidative stress, most of the existing work on DNA damage and repair mechanisms has been done in the context of cancer biology using cycling nonneuronal cells but not nondividing (i.e. postmitotic) neurons. Nevertheless, the identification of mutations in genes that encode proteins that function in DNA repair and DNA damage response in human hereditary DNA repair deficiency syndromes and ataxic disorders is establishing a mechanistic precedent that clearly links DNA damage and DNA repair abnormalities with progressive neurodegeneration. This review summarizes DNA damage and repair mechanisms and their potential relevance to the evolution of degeneration in postmitotic neurons.

Key findings

• DNA damage is a form of cell stress and injury that has been implicated in the pathogenesis of many neurologic disorders, including amyotrophic lateral sclerosis, Alzheimer disease, Down syndrome, Parkinson disease, cerebral ischemia, and head trauma.
• However, most data reveal only associations, and the role for DNA damage in direct mechanisms of neurodegeneration is vague with respect to being a definitive upstream cause of neuron cell death, rather than a consequence of the degeneration.
• Although neurons seem inclined to develop DNA damage during oxidative stress, most of the existing work on DNA damage and repair mechanisms has been done in the context of cancer biology using cycling nonneuronal cells but not nondividing (i.e. postmitotic) neurons.
• Nevertheless, the identification of mutations in genes that encode proteins that function in DNA repair and DNA damage response in human hereditary DNA repair deficiency syndromes and ataxic disorders is establishing a mechanistic precedent that clearly links DNA damage and DNA repair abnormalities with progressive neurodegeneration.
• This review summarizes DNA damage and repair mechanisms and their potential relevance to the evolution of degeneration in postmitotic neurons.

Why it matters

This review notes that DNA damage has been linked to Alzheimer disease and other neurologic disorders, but that most data show only associations and its role as a direct cause of neuron death remains unclear. It identifies no treatment or prevention for Alzheimer's disease.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1097/nen.0b013e31816ff780
• PubMed: 18431258
• Original source →
• Free full text: PubMed Central →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{martin2008-18431258,
  author  = {Martin, L. J.},
  title   = {{DNA damage and repair: relevance to mechanisms of neurodegeneration}},
  journal = {Journal of neuropathology and experimental neurology},
  year    = {2008},
  doi     = {10.1097/nen.0b013e31816ff780},
  pmid    = {18431258},
  url     = {https://doi.org/10.1097/nen.0b013e31816ff780}
}

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