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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 Clementi^{3, 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

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20103705-09$05.00/0

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