Cleavage of atrophin-1 at caspase site aspartic acid 109 modulates cytotoxicity

Lisa M. Ellerby, Rebecca L. Andrusiak, Cheryl L. Wellington, Abigail S Hackam, Stephanie S. Propp, Jonathan D. Wood, Alan H. Sharp, Russell L. Margolis, Christopher A. Ross, Guy S. Salvesen, Michael R. Hayden, Dale E. Bredesen

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

Dentatorubropallidoluysian atrophy (DRPLA) is one of eight autosomal dominant neurodegenerative disorders characterized by an abnormal CAG repeat expansion which results in the expression of a protein with a polyglutamine stretch of excessive length. We have reported recently that four of the gene products (hunting-tin, atrophin-1 (DRPLA), ataxin-3, and androgen receptor) associated with these open reading frame triplet repeat expansions are substrates for the cysteine protease cell death executioners, the caspases. This led us to hypothesize that caspase cleavage of these proteins may represent a common step in the pathogenesis of each of these four neurodegenerative diseases. Here we present evidence that caspase cleavage of atrophin-1 modulates cytotoxicity and aggregate formation. Cleavage of atrophin-1 at Asp109 by caspases is critical for cytotoxicity because a mutant atrophin-1 that is resistant to caspase cleavage is associated with significantly decreased toxicity. Further, the altered cellular localization within the nucleus and aggregate formation associated with the expanded form of atrophin-1 are completely suppressed by mutation of the caspase cleavage site at Asp109. These results provide support for the toxic fragment hypothesis whereby cleavage of atrophin-1 by caspases may be an important step in the pathogenesis of DRPLA. Therefore, inhibiting caspase cleavage of the polyglutamine-containing proteins may be a feasible therapeutic strategy to prevent cell death.

Original languageEnglish
Pages (from-to)8730-8736
Number of pages7
JournalJournal of Biological Chemistry
Volume274
Issue number13
DOIs
StatePublished - Mar 26 1999
Externally publishedYes

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Cytotoxicity
Caspases
Aspartic Acid
Atrophy
Cell death
Neurodegenerative Diseases
Cell Death
Neurodegenerative diseases
Trinucleotide Repeats
Proteins
Cysteine Proteases
Tin
atrophin-1
Poisons
Androgen Receptors
Open Reading Frames
Toxicity
Genes
Mutation
Substrates

ASJC Scopus subject areas

  • Biochemistry

Cite this

Ellerby, L. M., Andrusiak, R. L., Wellington, C. L., Hackam, A. S., Propp, S. S., Wood, J. D., ... Bredesen, D. E. (1999). Cleavage of atrophin-1 at caspase site aspartic acid 109 modulates cytotoxicity. Journal of Biological Chemistry, 274(13), 8730-8736. https://doi.org/10.1074/jbc.274.13.8730

Cleavage of atrophin-1 at caspase site aspartic acid 109 modulates cytotoxicity. / Ellerby, Lisa M.; Andrusiak, Rebecca L.; Wellington, Cheryl L.; Hackam, Abigail S; Propp, Stephanie S.; Wood, Jonathan D.; Sharp, Alan H.; Margolis, Russell L.; Ross, Christopher A.; Salvesen, Guy S.; Hayden, Michael R.; Bredesen, Dale E.

In: Journal of Biological Chemistry, Vol. 274, No. 13, 26.03.1999, p. 8730-8736.

Research output: Contribution to journalArticle

Ellerby, LM, Andrusiak, RL, Wellington, CL, Hackam, AS, Propp, SS, Wood, JD, Sharp, AH, Margolis, RL, Ross, CA, Salvesen, GS, Hayden, MR & Bredesen, DE 1999, 'Cleavage of atrophin-1 at caspase site aspartic acid 109 modulates cytotoxicity', Journal of Biological Chemistry, vol. 274, no. 13, pp. 8730-8736. https://doi.org/10.1074/jbc.274.13.8730
Ellerby, Lisa M. ; Andrusiak, Rebecca L. ; Wellington, Cheryl L. ; Hackam, Abigail S ; Propp, Stephanie S. ; Wood, Jonathan D. ; Sharp, Alan H. ; Margolis, Russell L. ; Ross, Christopher A. ; Salvesen, Guy S. ; Hayden, Michael R. ; Bredesen, Dale E. / Cleavage of atrophin-1 at caspase site aspartic acid 109 modulates cytotoxicity. In: Journal of Biological Chemistry. 1999 ; Vol. 274, No. 13. pp. 8730-8736.
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