亨廷顿蛋白
聚谷氨酰胺束
神经退行性变
亨廷顿病
亨廷顿蛋白
三核苷酸重复扩增
神经毒性
生物
突变
蛋白酶体
细胞生物学
遗传学
基因
分子生物学
化学
突变体
疾病
等位基因
医学
有机化学
病理
毒性
作者
David C. Rubinsztein,Jenny Carmichael
出处
期刊:Expert Reviews in Molecular Medicine
[Cambridge University Press]
日期:2003-08-22
卷期号:5 (20): 1-21
被引量:119
标识
DOI:10.1017/s1462399403006549
摘要
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HD gene. The expanded repeats are translated into an abnormally long polyglutamine tract close to the N-terminus of the HD gene product ('huntingtin'). Studies in humans and mouse models suggest that the mutation is associated with a deleterious gain-of-function. Several studies have suggested that the large huntingtin protein is cleaved to produce a shorter N-terminal fragment containing the polyglutamine expansion, and that the polyglutamine expansion causes the protein fragment to misfold and form aggregates (inclusions) in the nuclei and processes of neurons. It is likely that neurotoxicity is caused by the misfolded protein in its soluble form, and/or in aggregates, and/or in the process of aggregation. A wide range of potential mechanisms for neurotoxicity have been proposed, including caspase activation, dysregulation of transcriptional pathways, increased production of reactive oxygen species, and inhibition of proteasome activity. In this review we consider the current status of research in the field and possible mechanisms whereby the HD mutation might result in neurodegeneration.
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