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

Lisa M. Ellerby, Abigail S Hackam, Stephanie S. Propp, H. Michael Ellerby, Shahrooz Rabizadeh, Neil R. Cashman, Mark A. Trifiro, Leonard Pinsky, Cheryl L. Wellington, Guy S. Salvesen, Michael R. Hayden, Dale E. Bredesen

Research output: Contribution to journalArticle

203 Citations (Scopus)

Abstract

X-linked spinal and bulbar muscular atrophy (SBMA), Kennedy's disease, is a degenerative disease of the motor neurons that is associated with an increase in the number of CAG repeats encoding a polyglutamine stretch within the androgen receptor (AR). Recent work has demonstrated that the gene products associated with open reading frame triplet repeat expansions may be substrates for the cysteine protease cell death executioners, the caspases. However, the role that caspase cleavage plays in the cytotoxicity associated with expression of the disease-associated alleles is unknown. Here, we report the first conclusive evidence that caspase cleavage is a critical step in cytotoxicity; the expression of the AR with an expanded polyglutamine stretch enhances its ability to induce apoptosis when compared with the normal AR. The AR is cleaved by a caspase-3 subfamily protease at Asp146, and this cleavage is increased during apoptosis. Cleavage of the AR at Asp146 is critical for the induction of apoptosis by AR, as mutation of the cleavage 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 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 neurodegenerative diseases associated with polyglutamine repeat expansions.

Original languageEnglish
Pages (from-to)185-195
Number of pages11
JournalJournal of Neurochemistry
Volume72
Issue number1
DOIs
StatePublished - Jan 11 1999
Externally publishedYes

Fingerprint

X-Linked Bulbo-Spinal Atrophy
Androgen Receptors
Cytotoxicity
Caspases
Cell death
Cell Death
Apoptosis
Atrophic Muscular Disorders
Neurodegenerative diseases
Trinucleotide Repeats
Motor Neuron Disease
Mutation
Cysteine Proteases
Caspase 3
Neurodegenerative Diseases
Open Reading Frames
Neurons
Peptide Hydrolases
Genes
Alleles

Keywords

  • Aggregates
  • Androgen receptor
  • Caspase
  • Kennedy's disease
  • Triplet repeat disease

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Ellerby, L. M., Hackam, A. S., Propp, S. S., Ellerby, H. M., Rabizadeh, S., Cashman, N. R., ... Bredesen, D. E. (1999). Kennedy's disease: Caspase cleavage of the androgen receptor is a crucial event in cytotoxicity. Journal of Neurochemistry, 72(1), 185-195. https://doi.org/10.1046/j.1471-4159.1999.0720185.x

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

In: Journal of Neurochemistry, Vol. 72, No. 1, 11.01.1999, p. 185-195.

Research output: Contribution to journalArticle

Ellerby, LM, Hackam, AS, Propp, SS, Ellerby, HM, Rabizadeh, S, Cashman, NR, Trifiro, MA, Pinsky, L, Wellington, CL, Salvesen, GS, Hayden, MR & Bredesen, DE 1999, 'Kennedy's disease: Caspase cleavage of the androgen receptor is a crucial event in cytotoxicity', Journal of Neurochemistry, vol. 72, no. 1, pp. 185-195. https://doi.org/10.1046/j.1471-4159.1999.0720185.x
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. / Kennedy's disease : Caspase cleavage of the androgen receptor is a crucial event in cytotoxicity. In: Journal of Neurochemistry. 1999 ; Vol. 72, No. 1. pp. 185-195.
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