Genome instability and DNA repair in brain, ageing and neurological disease.

摘要

The stability of the genome of all organisms is constantly challenged by endogenous and exogenous agents that induce DNA lesions, genome instability, DNA recombination and other types of genotypic stress The nuclear and mitochondrial genomes of non-replicating cells of the brain are particularly vulnerable targets of DNA damage. DNA damage may have especially deleterious consequences in post-mitotic neuronal cells, because this cell pool is not normally regenerated by cellular proliferation. Recent studies of patients with Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, xeroderma pigmentosum (XP) and Huntington's disease suggest that oxidative stress and neuronal DNA damage are common features of these diseases (Kraemer et al., 2007; Trushina et al., 2007). Stroke patients also appear to be subject to increased oxidative DNA damage in neuronal cells and possible defects in DNA repair. However, the exact mechanism(s) by which oxidative DNA damage might causeneurodegeneration or neuronal cell death is poorly understood Intensive research in the area of DNA repair has led to rapid advances in understanding DNA repair mechanisms and the possible role of DNA repair in preventing cellular dysfunction and human disease. The specific role of DNA repair in the CNS is still unclear, but emerging techniques may make it possible to analyze the role of DNA repair in neuronal cells and nervous tissue in the near future. The theory that accumulated DNA damage contributes to neurodegeneration in brain can now be tested.