Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Mechanisms of disease: DNA repair defects and neurological disease. 1734 92

The accumulation of DNA damage has been widely implicated in premature aging and neurodegeneration. Progeroid syndromes with defects in the cellular response to DNA damage suggest that progressive genome instability represents an important aspect of the aging process. Moreover, most of the major neurodegenerative diseases are characterized by the accumulation of neuronal DNA damage, suggesting that impaired DNA repair mechanisms might be relevant to both premature aging and neurodegeneration. Two progeroid syndromes, Hutchinson-Gilford progeria syndrome and Werner's syndrome, are characterized by clinical features mimicking physiological aging at an early age and molecular studies have implicated decreased cell proliferation and altered DNA-damage responses as common causal mechanisms in the pathogenesis of both diseases. Defects in nucleotide excision repair cause three distinct human diseases: xeroderma pigmentosum, Cockayne's syndrome and trichothiodystrophy; each of them is characterized by premature onset of pathologies that overlap with those associated with old age in humans. Increasing evidence also suggests that an impaired DNA repair, particularly the base excision repair pathway, might play a fundamental role in the development of age-related neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington' s disease. Here, we review the current knowledge on the role of DNA repair in premature aging and neurodegenerative diseases.
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PMID:DNA repair in premature aging disorders and neurodegeneration. 2029 65