Dorotea Rigamonti, Johannes H. Bauer, Claudio De-Fraja, Luciano Conti, Simonetta Sipione, Clara Sciorati, Emilio Clementi, Abigail Hackam, Michael R. Hayden, Yong Li, Jillian K. Cooper, Christopher A. Ross, Stefano Govoni, Claudius Vincenz, Elena Cattaneo

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.