Wild-type Huntingtin protects from apoptosis upstream of caspase-3

Expansion of a polyglutamine sequence in the N terminus of huntingtin is th e gain-of-function event that causes Huntington's disease. This mutation af fects primarily the medium-size spiny neurons of the striatum. Huntingtin i s expressed in many neuronal and non-neuronal cell types, implying a more g eneral function for the wild-type protein. Here we report that wild-type hu ntingtin acts by protecting CNS cells from a variety of apoptotic stimuli, including serum withdrawal, death receptors, and pro-apoptotic Bcl-2 homolo gs. This protection may take place at the level of caspase-9 activation. Th e 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.