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.
Highlights
Huntingtin is a 348-kDa cytoplasmic protein that is important for cell survival [1,2,3,4,5]
Proteolysis of Endogenous Wild-type Huntingtin in Primary Neurons Follows Calcium Influx—We aimed at analyzing whether endogenous huntingtin expressed in cortical neurons undergoes proteolysis induced by calcium entry into the cells
We show that changes in calcium homeostasis evoked by glutamate and 3-nitropropionic acid (3-NP) lead to calpain-dependent proteolysis of endogenous wild-type huntingtin in cortical neurons
Summary
Huntingtin is a 348-kDa cytoplasmic protein that is important for cell survival [1,2,3,4,5]. Exposure of primary neurons to glutamate or 3-nitropropionic acid increases intracellular calcium concentration, leading to loss of intact full-length wild-type huntingtin. We aimed at evaluating whether endogenous wild-type huntingtin found in primary cortical neurons could be cleaved by stimuli that increase intracellular calcium levels, leading to calpain activation.
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