Wild-Type Huntingtin Protects from Apoptosis Upstream of Caspase-3

作者：Dorotea Rigamonti, Johannes H. Bauer, Claudio De‐Fraja, Luciano Conti, Simonetta Sipione, Clara Sciorati, Emilio Clementi, Abigail S. Hackam, Michael R. Hayden, Yong Li, Jillian K. Cooper, Christopher A. Ross, Stefano M. Govoni, Claudius Vincenz, Elena F. Cattaneo · 发表于：Journal of Neuroscience · 年份：2000 · DOI：10.1523/jneurosci.20-10-03705.2000 · 被引用次数：401 · 研究领域：Genetic Neurodegenerative Diseases、Mitochondrial Function and Pathology、Ion channel regulation and function

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.