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Kennedy's Disease
Author(s) -
Ellerby Lisa M.,
Hackam Abigail S.,
Propp Stephanie S.,
Ellerby H. Michael,
Rabizadeh Shahrooz,
Cashman Neil R.,
Trifiro Mark A.,
Pinsky Leonard,
Wellington Cheryl L.,
Salvesen Guy S.,
Hayden Michael R.,
Bredesen Dale E.
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.0720185.x
Subject(s) - caspase , programmed cell death , cleavage (geology) , biology , apoptosis , microbiology and biotechnology , spinal and bulbar muscular atrophy , proteases , caspase 3 , nlrp1 , androgen receptor , genetics , biochemistry , enzyme , paleontology , prostate cancer , cancer , fracture (geology)
: 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 Asp 146 , and this cleavage is increased duringapoptosis. Cleavage of the AR at Asp 146 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 Asp 146 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.