Background Abnormal copper accumulation in the HD brain was reported more than 15 years ago and recent findings show a significant induction of several copper regulatory genes during HD. Furthermore, copper binds to the N terminal of huntingtin supporting the involvement of abnormal copper metabolism in HD.

Results and conclusions We demonstrate that in vitro copper accelerates the fibrillisation of recombinant N terminal fragments of huntingtin with an expanded polyQ stretch (httEx1). Because we also find that copper increases httEx1 aggregation and toxicity in mammalian cells, we investigated whether overexpression of genes involved in copper metabolism, notably metallothioneins (MTs) known to bind copper, protect against httEx1 toxicity. Using a yeast model of HD, we show that overexpression of several genes involved in copper metabolism reduces polyQ mediated toxicity. Overexpression of MT-3 in mammalian cells also suppresses polyQ aggregation and toxicity. We propose that copper binding and/or chaperoning proteins, especially MTs, are potential therapeutic targets for HD.