F. Saudou et al., HUNTINGTIN ACTS IN THE NUCLEUS TO INDUCE APOPTOSIS BUT DEATH DOES NOTCORRELATE WITH THE FORMATION OF INTRANUCLEAR INCLUSIONS, Cell (Cambridge), 95(1), 1998, pp. 55-66
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.