Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells

Cheryl L. Wellington, Roshni Singaraja, Lisa Ellerby, Jane Savill, Sophie Roy, Blair Leavitt, Elena Cattaneo, Abigail Hackam, Alan Sharp, Nancy Thornberry, Donald W. Nicholson, Dale E. Bredesen, Michael R. Hayden

Research output: Contribution to journalArticle

279 Scopus citations

Abstract

Huntington's disease is a neurodegenerative disorder caused by CAG expansion that results in expansion of a polyglutamine tract at the extreme N terminus of huntingtin (htt). htt with polyglutamine expansion is proapoptotic in different cell types. Here, we show that caspase inhibitors diminish the toxicity of htt. Additionally, we define htt itself as an important caspase substrate by generating a site-directed htt mutant that is resistant to caspase-3 cleavage at positions 513 and 530 and to caspase-6 cleavage at position 586. In contrast to clearable htt, caspase-resistant htt with an expanded polyglutamine tract has reduced toxicity in apoptotically stressed neuronal and nonneuronal cells and forms aggregates at a much reduced frequency. These results suggest that inhibiting caspase cleavage of htt may therefore be of potential therapeutic benefit in Huntington's disease.

Original languageEnglish (US)
Pages (from-to)19831-19838
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number26
DOIs
StatePublished - Jun 30 2000
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Wellington, C. L., Singaraja, R., Ellerby, L., Savill, J., Roy, S., Leavitt, B., Cattaneo, E., Hackam, A., Sharp, A., Thornberry, N., Nicholson, D. W., Bredesen, D. E., & Hayden, M. R. (2000). Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells. Journal of Biological Chemistry, 275(26), 19831-19838. https://doi.org/10.1074/jbc.M001475200