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

Huntingtos’s disease (HD) is caused by a polyglutamine expansion in the amin-terminal region of huntingtin. Mutant huntingtin is proteolytically cleaved by caspases, generating amino-terminal aggregates wich are toxic for cells. Addition of calpains to total brain homogenates also leads to cleavage of zild-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 neuroprotecive activity.