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Previous Article | Next Article
The Journal of Neuroscience, May 15, 2000, 20(10):3705-3713
Wild-Type Huntingtin Protects from Apoptosis Upstream of Caspase-3
Dorotea Rigamonti1, Johannes H. Bauer2, Claudio De-Fraja1, Luciano Conti1, Simonetta Sipione1, Clara Sciorati3, Emilio Clementi3, 4, Abigail Hackam5, Michael R. Hayden5, Yong Li2, Jillian K. Cooper6, Christopher A. Ross6, Stefano Govoni7, Claudius Vincenz2, and Elena Cattaneo1 1 Institute of Pharmacological Sciences, University of Milano, 20133 Milano, Italy, 2 Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109-0726, 3 Department of Biotechnology, San Raffaele Hospital, Milano, Italy, 4 Department of Pharmacobiology, University of Calabria, 87036 Rende, Italy, 5 University of British Columbia, V52 4H4 Vancouver, British Columbia, Canada, 6 Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland 21025, and 7 Institute of Pharmacology, University of Pavia, 27100 Pavia, Italy
Expansion of a polyglutamine sequence in the N terminus of huntingtin is the gain-of-function event that causes Huntington's disease. This mutation affects primarily the medium-size spiny neurons of the striatum. Huntingtin is expressed in many neuronal and non-neuronal cell types, implying a more general function for the wild-type protein. Here we report that wild-type huntingtin acts by protecting CNS cells from a variety of apoptotic stimuli, including serum withdrawal, death receptors, and pro-apoptotic Bcl-2 homologs. This protection may take place at the level of caspase-9 activation. The full-length protein also modulates the toxicity of the poly-Q expansion. Cells expressing full-length mutant protein are susceptible to fewer death stimuli than cells expressing truncated mutant huntingtin.
Key words: huntingtin; CAG; caspases; survival; CNS cells; Huntington's disease
Copyright © 2000 Society for Neuroscience 0270-6474/00/20103705-09$05.00/0
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