Caspase-8 is required for cell death induced by expanded polyglutamine repeats

We show here that caspase-8 is required for the death of primary rat neuron s induced by an expanded polyglutamine repeat (Q79). Expression of Q79 recr uited and activated caspase-8. Inhibition of caspase-8 blocked polyglutamin e-induced cell death. Coexpression of Q79 with the caspase inhibitor CrmA, a dominant-negative mutant of FADD (FADD DN), Bcl-2, or Bcl-x(L), but not a n N-terminally tagged Bcl-x(L), prevented the recruitment of caspase-8 and inhibited polyglutamine-induced cell death. Furthermore, Western blot analy sis revealed the presence of activated caspase-8 in the insoluble fraction of affected brain regions from Huntington's disease (HD) patients but not i n those from neurologically unremarkable controls, suggesting the relocatio n and activation of caspase-8 during the pathogenesis of HD. These results suggest an essential role of caspase-8 in HD-related neural degenerative di seases.