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.
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Review Article|
May 14 2008
Huntington's disease: from pathology and genetics to potential therapies
Sara Imarisio;
Sara Imarisio
*Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, U.K.
†Department of Genetics, University of Cambridge, Cambridge CB2 3EH, U.K.
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Jenny Carmichael;
Jenny Carmichael
*Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, U.K.
†Department of Genetics, University of Cambridge, Cambridge CB2 3EH, U.K.
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Viktor Korolchuk;
Viktor Korolchuk
*Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, U.K.
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Chien-Wen Chen;
Chien-Wen Chen
*Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, U.K.
†Department of Genetics, University of Cambridge, Cambridge CB2 3EH, U.K.
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Shinji Saiki;
Shinji Saiki
*Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, U.K.
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Claudia Rose;
Claudia Rose
*Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, U.K.
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Gauri Krishna;
Gauri Krishna
*Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, U.K.
†Department of Genetics, University of Cambridge, Cambridge CB2 3EH, U.K.
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Janet E. Davies;
Janet E. Davies
*Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, U.K.
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Evangelia Ttofi;
Evangelia Ttofi
*Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, U.K.
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Benjamin R. Underwood;
Benjamin R. Underwood
*Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, U.K.
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David C. Rubinsztein
David C. Rubinsztein
1
*Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, U.K.
1To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
November 29 2007
Revision Received:
March 19 2008
Accepted:
March 19 2008
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 412 (2): 191–209.
Article history
Received:
November 29 2007
Revision Received:
March 19 2008
Accepted:
March 19 2008
Citation
Sara Imarisio, Jenny Carmichael, Viktor Korolchuk, Chien-Wen Chen, Shinji Saiki, Claudia Rose, Gauri Krishna, Janet E. Davies, Evangelia Ttofi, Benjamin R. Underwood, David C. Rubinsztein; Huntington's disease: from pathology and genetics to potential therapies. Biochem J 1 June 2008; 412 (2): 191–209. doi: https://doi.org/10.1042/BJ20071619
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