Kennedy's disease: Caspase cleavage of the androgen receptor is a crucial event in cytotoxicity

X-linked spinal and bulbar muscular atrophy (SBMA), Kennedy's disease, is a degenerative disease of the motor neurons that is associated with an incre ase in the number of CAG repeats encoding a polyglutamine stretch within th e androgen receptor (AR). Recent work has demonstrated that the gene produc ts associated with open reading frame triplet repeat expansions may be subs trates for the cysteine protease cell death executioners, the caspases, How ever, the role that caspase cleavage plays in the cytotoxicity associated w ith expression of the disease-associated alleles is unknown. Here. we repor t the first conclusive evidence that caspase cleavage is a critical step in cytotoxicity; the expression of the AR with an expanded polyglutamine stre tch enhances its ability to induce apoptosis when compared with the normal AR. The AR is cleaved by a caspase-3 subfamily protease at Asp(146), and th is cleavage is increased during apoptosis, Cleavage of the AR at Asp(146) i s critical for th, induction of apoptosis by AR, as mutation of the cleavag e site blocks the ability of the AR to induce cell death. Further, mutation of the caspase cleavage site at Asp146 blocks the ability of the SBMA AR t o form perinuclear aggregates. These studies define a fundamental role for caspase cleavage in the induction of neural cell death by proteins displayi ng expanded polyglutamine tracts, and therefore suggest a strategy that may be useful to treat neurodegenerative diseases associated with polyglutamin e repeat expansions.