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Mechanisms of Disease: DNA repair defects and neurological disease

Abstract

In this Review, familial and sporadic neurological disorders reported to have an etiological link with DNA repair defects are discussed, with special emphasis placed on the molecular link between the disease phenotype and the precise DNA repair defect. Of the 15 neurological disorders listed, some of which have symptoms of progeria, six—spinocerebellar ataxia with axonal neuropathy-1, Huntington's disease, Alzheimer's disease, Parkinson's disease, Down syndrome and amyotrophic lateral sclerosis—seem to result from increased oxidative stress, and the inability of the base excision repair pathway to handle the damage to DNA that this induces. Five of the conditions (xeroderma pigmentosum, Cockayne's syndrome, trichothiodystrophy, Down syndrome, and triple-A syndrome) display a defect in the nucleotide excision repair pathway, four (Huntington's disease, various spinocerebellar ataxias, Friedreich's ataxia and myotonic dystrophy types 1 and 2) exhibit an unusual expansion of repeat sequences in DNA, and four (ataxia-telangiectasia, ataxia-telangiectasia-like disorder, Nijmegen breakage syndrome and Alzheimer's disease) exhibit defects in genes involved in repairing double-strand breaks. The current overall picture indicates that oxidative stress is a major causative factor in genomic instability in the brain, and that the nature of the resulting neurological phenotype depends on the pathway through which the instability is normally repaired.

Key Points

  • The native structure of genomic DNA can be damaged in many ways, both by external agents and from within the cell as a consequence of normal metabolism

  • In an effort to maintain their genomic integrity, organisms have evolved a number of pathways to repair DNA damage

  • Mutations in genes coding for proteins involved in DNA repair pathways can lead to abnormal phenotypes, including neurological disorders, cancer and premature aging; many such conditions are found to have an etiological link to defects in one or more DNA repair pathways

  • In a postmitotic organ such as the brain, the base excision repair pathway—a conserved mode of DNA repair that deals with the oxidative damage that can result from internal forces—has an important role, and could be a viable candidate for therapeutic targeting

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Figure 1: An outline of the nucleotide excision repair pathway, which includes global genomic repair (1B) and transcription-coupled repair (1A)
Figure 2: Outline of base excision repair showing the two subpathways: (A) the 'short-patch' or single-nucleotide pathway, and (B) the 'long-patch' pathway

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Acknowledgements

KS Rao would like to acknowledge the help of his colleague Umakanth Swain in drawing the original artwork for figure 1.

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Subba Rao, K. Mechanisms of Disease: DNA repair defects and neurological disease. Nat Rev Neurol 3, 162–172 (2007). https://doi.org/10.1038/ncpneuro0448

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