Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract

Cheryl L. Wellington, Lisa M. Ellerby, Abigail S. Hackam, Russell L. Margolis, Mark A. Trifiro, Roshni Singaraja, Krista McCutcheon, Guy S. Salvesen, Stephanie S. Propp, Michael Bromm, Kathleen J. Rowland, Taiqi Zhang, Dita Rasper, Sophie Roy, Nancy Thornberry, Leonard Pinsky, Akira Kakizuka, Christopher A. Ross, Donald W. Nicholson, Dale E. BredesenMichael R. Hayden

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Abstract

The neurodegenerative disease Huntington disease, dentatorubropallidoluysian atrophy, spinocerebellar atrophy type 3, and spinal bulbar muscular atrophy are caused by expansion of a polyglutamine tract within their respective gene products. There is increasing evidence that generation of truncated proteins containing an expanded polyglutamine tract may be a key step in the pathogenesis of these disorders. We now report that, similar to huntingtin, atrophin-1, ataxin-3, and the androgen receptor are cleaved in a apoptotic extracts. Furthermore, each of these proteins is cleaved by one or more purified caspases, cysteine proteases involved in apoptotic death. The CAG length does not modulate susceptibility to cleavage of any of the full-length proteins. Our results suggest that by generation of truncated polyglutamine-containing proteins, caspase cleavage may represent a common step in the pathogenesis of each of these neurodegenerative diseases.

Original languageEnglish (US)
Pages (from-to)9158-9167
Number of pages10
JournalJournal of Biological Chemistry
Volume273
Issue number15
DOIs
StatePublished - Apr 10 1998
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Wellington, C. L., Ellerby, L. M., Hackam, A. S., Margolis, R. L., Trifiro, M. A., Singaraja, R., McCutcheon, K., Salvesen, G. S., Propp, S. S., Bromm, M., Rowland, K. J., Zhang, T., Rasper, D., Roy, S., Thornberry, N., Pinsky, L., Kakizuka, A., Ross, C. A., Nicholson, D. W., ... Hayden, M. R. (1998). Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. Journal of Biological Chemistry, 273(15), 9158-9167. https://doi.org/10.1074/jbc.273.15.9158