Calcium-dependent cleavage of endogenous wild-type huntingtin in primary cortical neurons |
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Authors: | Goffredo Donato Rigamonti Dorotea Tartari Marzia De Micheli Alberto Verderio Claudia Matteoli Michela Zuccato Chiara Cattaneo Elena |
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Institution: | Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milan, Milano, Italy. |
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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. |
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