期刊
HUMAN MOLECULAR GENETICS
卷 9, 期 4, 页码 503-513出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/9.4.503
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资金
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [P50NS016367, P01NS016367, R01NS032765] Funding Source: NIH RePORTER
- NINDS NIH HHS [NS32765, NS16367] Funding Source: Medline
Huntington's disease (HD) is caused by an expanded N-terminal glutamine tract that endows huntingtin with a striatal-selective structural property ultimately toxic to medium spiny neurons. In precise genetic models of juvenile HD, Hdh(Q92) and Hdh(Q111) knock-in mice, long polyglutamine segments change huntingtin's physical properties, producing HD-like in vivo correlates in the striatum, including nuclear localization of a version of the full-length protein predominant in medium spiny neurons, and subsequent formation of N-terminal inclusions and insoluble aggregate. These changes show glutamine length dependence and dominant inheritance with recruitment of wild-type protein, critical features of the altered HD property that strongly implicate them in the HD disease process and that suggest alternative pathogenic scenarios: the effect of the glutamine tract may act by altering interaction with a critical cellular constituent or by depleting a form of huntingtin essential to medium spiny striatal neurons.
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