ISSN:
1471-4159
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
Abstract : X-linked spinal and bulbar muscular atrophy (SBMA),Kennedy's disease, is a degenerative disease of the motor neurons that isassociated with an increase in the number of CAG repeats encoding apolyglutamine stretch within the androgen receptor (AR). Recent work hasdemonstrated that the gene products associated with open reading frame tripletrepeat expansions may be substrates for the cysteine protease cell deathexecutioners, the caspases. However, the role that caspase cleavage plays inthe cytotoxicity associated with expression of the disease-associated allelesis unknown. Here, we report the first conclusive evidence that caspasecleavage is a critical step in cytotoxicity ; the expression of the AR with anexpanded polyglutamine stretch enhances its ability to induce apoptosis whencompared with the normal AR. The AR is cleaved by a caspase-3 subfamilyprotease at Asp146, and this cleavage is increased duringapoptosis. Cleavage of the AR at Asp146 is critical for theinduction of apoptosis by AR, as mutation of the cleavage site blocks theability of the AR to induce cell death. Further, mutation of the caspasecleavage site at Asp146 blocks the ability of the SBMA AR to form perinuclear aggregates. These studies define a fundamental role for caspase cleavage in the induction of neural cell death by proteins displaying expanded polyglutamine tracts, and therefore suggest a strategy that may be useful to treat neurodegenrative diseases associated with polyglutamine repeat expansions.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1046/j.1471-4159.1999.0720185.x
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