Extended polyglutamine selectively interacts with caspase-8 and-10 in nuclear aggregates

A growing number of inherited neurodegenerative disorders, including Huntin gton's disease, have been shown to be caused by the expansion of CAG/polygl utamine repeats. The molecular mechanism underlying these disorders, howeve r, has yet to be clarified. We and others previously demonstrated that casp ase-8 was activated by proteolysis in association with the expression of ex tended 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 activa ted, but caspase-9 was not, Caspase-8 and -10 were recruited into nuclear a ggregates of extended polyglutamine, where at least a fraction of these cas pases was converted to the activated forms. Caspase-8 and -10 were co immun oprecipitated with polyglutamine only when the polyglutamine was pathologic ally extended, whereas caspase-2, -3, -6, -7 and -9 were not co-immunopreci pitated with polyglutamine regardless of its size. A dominant-negative form of caspase-8 with a mutation at the catalytic cysteine residue inhibited p olyglutamine-mediated nuclear apoptotic phenotype, These results suggest th at caspase-8 and -10 are autoactivated as a result of close proximity of th e proforms of these molecules that occurs due to aggregate formation, which reveals a novel toxic gain-of-function mechanism for the pathogenesis of C AG-repeat disorders.