Huntington's disease: from pathology and genetics to potential therapies

被引:289
作者
Imarisio, Sara [1 ,2 ]
Carmichael, Jenny [1 ,2 ]
Korolchuk, Viktor [1 ]
Chen, Chien-Wen [1 ,2 ]
Saiki, Shinji [1 ]
Rose, Claudia [1 ]
Krishna, Gauri [1 ,2 ]
Davies, Janet E. [1 ]
Ttofi, Evangelia [1 ]
Underwood, Benjamin R. [1 ]
Rubinsztein, David C. [1 ]
机构
[1] Univ Cambridge, Dept Med Genet, Cambridge Inst Med Res, Addenbrookes Hosp, Cambridge CB2 0XY, England
[2] Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England
基金
英国医学研究理事会; 英国惠康基金;
关键词
huntingtin; Huntington's disease; neurodegenerative disease; polyglutamine tract;
D O I
10.1042/BJ20071619
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Huntington's disease (HD) is a devastating autosomal dominant neurodegenerative disease caused by a CAG trinucleotide repeat expansion encoding an abnormally long polyglutamine tract in the huntingtin protein. Much has been learnt since the mutation was identified in 1993. We review the functions of wild-type huntingtin. Mutant huntingtin may cause toxicity via a range of different mechanisms. The primary consequence of the mutation is to confer a toxic gain of function on the mutant protein and this may be modified by certain normal activities that are impaired by the mutation. It is likely that the toxicity of mutant huntingtin is revealed after a series of cleavage events leading to the production of N-terminal huntingtin fragment(s) containing the expanded polyglutamine tract. Although aggregation of the mutant protein is a hallmark of the disease, the role of aggregation is complex and the arguments for protective roles of inclusions are discussed. Mutant huntingtin may mediate some of its toxicity in the nucleus by perturbing specific transcriptional pathways. HD may also inhibit mitochondrial function and proteasome activity. Importantly, not all of the effects of mutant huntingtin may be cell-autonomous, and it is possible that abnormalities in neighbouring neurons and glia may also have an impact on connected cells. It is likely that there is still much to learn about mutant huntingtin toxicity, and important insights have already come and may still come from chemical and genetic screens. Importantly, basic biological studies in HD have led to numerous potential therapeutic strategies.
引用
收藏
页码:191 / 209
页数:19
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