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Originally published In Press as doi:10.1074/jbc.C200353200 on August 27, 2002

J. Biol. Chem., Vol. 277, Issue 42, 39594-39598, October 18, 2002
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Calcium-dependent Cleavage of Endogenous Wild-type Huntingtin in Primary Cortical Neurons*

Donato GoffredoDagger §, Dorotea RigamontiDagger §, Marzia TartariDagger , Alberto De MicheliDagger , Claudia Verderio, Michela Matteoli, Chiara ZuccatoDagger , and Elena CattaneoDagger ||

From the Dagger  Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milan and the  National Council of Research Institute of Neuroscience, Department of Medical Pharmacology, University of Milan, 20133 Milano, Italy

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.

* This study was supported by Telethon, Italy (E840); the Huntington's Disease Society of America, New York; the Hereditary Disease Foundation, Los Angeles; and Ministero dell'Universita' e della Ricerca Scientifica, Italy (Miur MM06278849-005) to E. C.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed equally to the study.

|| To whom correspondence should be addressed: Dept. of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milan, Via Balzaretti 9, 20133 Milano, Italy. Tel.: 39-02-50318333; Fax: 39-02-50318284; E-mail: elena.cattaneo@ unimi.it.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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