HD (Huntington’s disease) is caused by a polyQ (polyglutamine) expansion in the huntingtin protein, which<br/>leads to protein misfolding and aggregation of this protein. Abnormal copper accumulation in the HD brain<br/>was first reported more than 15 years ago. Recent findings show that copper-regulatory genes are induced<br/>during HD and copper binds to an N-terminal fragment of huntingtin, supporting the involvement of abnormal<br/>copper metabolism in HD. <br/><br/>We have demonstrated that in vitro copper accelerates the fibrillization of an N-terminal fragment of huntingtin with an expanded polyQ stretch (httExon1). As we found that copper also increases polyQ aggregation and toxicity in mammalian cells expressing httExon1, we investigated further<br/>whether overexpression of genes involved in copper metabolism, notably MTs (metallothioneins) known to<br/>bind copper, protect against httExon1 toxicity. <br/><br/>Using a yeastmodel of HD,we have shown that overexpression<br/>of several genes involved in copper metabolism reduces polyQ-mediated toxicity. Overexpression of MT-3<br/>in mammalian cells significantly reduced polyQ aggregation and toxicity. We propose that copper-binding<br/>and/or -chaperoning proteins, especially MTs, are potential therapeutic targets for HD
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