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Metallothioneins and copper metabolism are candidate therapeutic targets in huntington’s disease

By Sarah L. Hands, Robert Mason, M. Umar Sajjad, Flaviano Giorgini and Andreas Wyttenbach

Abstract

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

Topics: QA
Year: 2010
OAI identifier: oai:eprints.soton.ac.uk:145343
Provided by: e-Prints Soton

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