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Prog Mol Biol Transl Sci. 2012;107:189-214. doi: 10.1016/B978-0-12-385883-2.00010-2.

Huntington disease and the huntingtin protein.

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1
Hope Center for Neurological Diseases, Knight-Alzheimer Disease Research Center, Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA.

Abstract

Huntington disease (HD) is a devastating neurodegenerative disease that derives from CAG repeat expansion in the huntingtin gene. The clinical syndrome consists of progressive personality changes, movement disorder, and dementia and can develop in children and adults. The huntingtin protein is required for human development and normal brain function. It is subject to posttranslational modification, and some events, such as phosphorylation, can play an enormous role in regulating toxicity of the huntingtin protein. The function of huntingtin in the cell is unknown, and it may play a role as a scaffold. Multiple mouse models of HD have now been created with fragments and full-length protein. The models show variable fidelity to the disease in terms of genetics, pathology, and rates of progression. Pathogenesis of HD involves cleavage of the protein and is associated with neuronal accumulation of aggregated forms. The potential mechanisms of neurodegeneration are myriad, including primary effects of protein homeostasis, gene expression, and mitochondrial dysfunction. Specific therapeutic approaches are similarly varied and include efforts to reduce huntingtin gene expression, protein accumulation, and protein aggregation.

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