Human Molecular Genetics, Vol 5, 1431-1435, Copyright © 1996 by Oxford University Press
J Nasir, YP Goldberg and MR Hayden
The mutation underlying Huntington disease (HD) is CAG expansion beyond 35
repeats within a novel gene. Recently, new insights into the role of the HD
protein (huntingtin) in the pathogenesis of HD have emerged. The CAG is
translated and expression of mutant huntingtin is essential for neuronal
death. Huntingtin is crucial for normal development and may be regarded as
a cell survival gene. Huntingtin is specifically cleaved during apoptosis
by a key cysteine protease, apopain, known to play a pivotal role in
apoptotic cell death. The rate of cleavage is enhanced by longer
polyglutamine tracts, suggesting that inappropriate apoptosis underlies HD.
Recently, three proteins have been identified and have been shown
specifically to interact with huntingtin, two of these interactions being
influenced by CAG length. Several different approaches to develop an animal
model for HD include cDNA and YAC transgenics, as well as 'knock-in'
strategies. Such a model will be critical for the understanding of the
natural history of HD and for the testing of new therapeutic modalities.
REVIEWS
Huntington disease: new insights into the relationship between CAG expansion and disease
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
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