A growing number of inherited
neurodegenerative disorders, including
Huntington's disease, have been shown to be caused by the expansion of CAG/
polyglutamine repeats. The molecular mechanism underlying these disorders, however, has yet to be clarified. We and others previously demonstrated that
caspase-8 was activated by proteolysis in association with the expression of extended
polyglutamine. Here, we further analyzed the selectivity of
caspases in the process mediated by extended
polyglutamine. Among upstream
caspases,
caspase-10, a close homolog of
caspase-8, was also proteolytically activated, but
caspase-9 was not.
Caspase-8 and -10 were recruited into nuclear aggregates of extended
polyglutamine, where at least a fraction of these
caspases was converted to the activated forms.
Caspase-8 and -10 were co-immunoprecipitated with
polyglutamine only when the
polyglutamine was pathologically extended, whereas
caspase-2, -3, -6, -7 and -9 were not co-immunoprecipitated with
polyglutamine regardless of its size. A dominant-negative form of
caspase-8 with a mutation at the catalytic
cysteine residue inhibited
polyglutamine-mediated nuclear apoptotic phenotype. These results suggest that
caspase-8 and -10 are autoactivated as a result of close proximity of the proforms of these molecules that occurs due to aggregate formation, which reveals a novel toxic gain-of-function mechanism for the pathogenesis of CAG-repeat disorders.