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A more recent version of this article appeared on October 11, 2002
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C200353200v1
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Papers In Press, published online ahead of print August 27, 2002
J. Biol. Chem, 10.1074/jbc.C200353200
Submitted on June 12, 2002
Revised on August 14, 2002
Accepted on August 27, 2002

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, and Elena Cattaneo

Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milano, Milano 20133

Corresponding Author: elena.cattaneo{at}unimi.it

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 which are toxic for cells. 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. Loss of intact full-length wild-type huntingtin occurs also after exposure of primary neurons to glutamate or 3-nitropropionic acid, which lead to increased intracellular calcium concentration, and could be prevented by calcium chelators and calpains inhibitors. Degradation of wild-type huntingtin by calcium-dependent proteases thus occurs in HD neurons leading to loss of wild-type huntingtin neuroprotective activity.


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