HUNTINGTIN ACTS IN THE NUCLEUS TO INDUCE APOPTOSIS BUT DEATH DOES NOTCORRELATE WITH THE FORMATION OF INTRANUCLEAR INCLUSIONS

The mechanisms by which mutant huntingtin induces neurodegeneration we re investigated using a cellular model that recapitulates features of neurodegeneration seen in Huntington's disease. When transfected into cultured striatal neurons, mutant huntingtin induces neurodegeneration by an apoptotic mechanism. Antiapoptotic compounds or neurotrophic fa ctors protected neurons against mutant huntingtin. Blocking nuclear lo calization of mutant huntingtin suppressed its ability to form intranu clear inclusions and to induce neurodegeneration. However, the presenc e of inclusions did not correlate with huntingtin-induced death. The e xposure of mutant huntingtin-transfected striatal neurons to condition s that suppress the formation of inclusions resulted in an increase in mutant huntingtin-induced death. These findings suggest that mutant h untingtin acts within the nucleus to induce neurodegeneration. However , intranuclear inclusions may reflect a cellular mechanism to protect against huntingtin-induced cell death.