DNA repair deficiency and neurological disease

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Abstract
DNA repair is crucial for nervous system genesis and function. Mutations in various DNA repair factors can lead to human diseases that are characterized by pronounced neuropathology. Biochemically distinct DNA repair pathways have evolved to repair specific DNA lesions. Requirements for individual DNA repair factors in the nervous system depend on the developmental stage. A main question associated with inherited human DNA repair-deficiency syndromes is the nature, source and tissue-specific outcomes of endogenous DNA damage in the nervous system. Oxidative stress-induced DNA damage is likely to be an important aetiologic agent in these diseases. DNA repair deficiency can lead to different human diseases, typified by microcephaly, reflecting increased cell death during development, or neurodegeneration, from later progressive cellular demise due to accumulated developmental damage or interference with transcription. In some cases, defects in the same DNA repair pathway can result in different neuropathology depending on the particular repair factor targeted or the exact nature of the mutation. For example, defects in nucleotide excision repair can lead to clinically distinct diseases. Because DNA repair deficiency syndromes are congenital, designing drugs to treat these debilitating diseases will require a molecular understanding of the consequences of DNA damage in the developing and mature brain.