Calcium-dependent cleavage of endogenous wild-type huntingtin in primary cortical neurons

Donato Goffredo, Dorotea Rigamonti, Marzia Tartari, Alberto De Micheli, Claudia Verderio, Michela Matteoli, Chiara Zuccato, Elena Cattaneo

Research output: Contribution to journalArticlepeer-review

Abstract

Huntington's disease (HD) is caused by a polyglutamine expansion in the amino-terminal region of huntingtin. Mutant huntingtin is proteolytically cleaved by caspases, generating amino-terminal aggregates that are toxic for cells. The addition of calpains to total brain homogenates also leads to cleavage of wild-type huntingtin, indicating that proteolysis of mutant and wild-type huntingtin may play a role in HD. Here we report that endogenous wild-type huntingtin is promptly cleaved by calpains in primary neurons. Exposure of primary neurons to glutamate or 3-nitropropionic acid increases intracellular calcium concentration, leading to loss of intact full-length wild-type huntingtin. This cleavage could be prevented by calcium chelators and calpain inhibitors. Degradation of wild-type huntingtin by calcium-dependent proteases thus occurs in HD neurons, leading to loss of wild-type huntingtin neuroprotective activity.

Original languageEnglish
Pages (from-to)39594-39598
Number of pages5
JournalJournal of Biological Chemistry
Volume277
Issue number42
DOIs
Publication statusPublished - Oct 18 2002

ASJC Scopus subject areas

  • Biochemistry

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