Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/8037
Title: Metallothioneins and copper metabolism are candidate therapeutic targets in Huntington's disease
Authors: Hands, Sarah L.
Mason, Robert
Sajjad, M. Umar
Giorgini, Flaviano
Wyttenbach, Andreas
First Published: Apr-2010
Publisher: Portland Press
Citation: Biochemical Society Transactions, 2010, 38 (2), pp. 552-558.
Abstract: HD (Huntington's disease) is caused by a polyQ (polyglutamine) expansion in the huntingtin protein, which leads to protein misfolding and aggregation of this protein. Abnormal copper accumulation in the HD brain was first reported more than 15 years ago. Recent findings show that copper-regulatory genes are induced during HD and copper binds to an N-terminal fragment of huntingtin, supporting the involvement of abnormal copper metabolism in HD. 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 whether overexpression of genes involved in copper metabolism, notably MTs (metallothioneins) known to bind copper, protect against httExon1 toxicity. Using a yeast model of HD, we have shown that overexpression of several genes involved in copper metabolism reduces polyQ-mediated toxicity. Overexpression of MT-3 in mammalian cells significantly reduced polyQ aggregation and toxicity. We propose that copper-binding and/or -chaperoning proteins, especially MTs, are potential therapeutic targets for HD.
DOI Link: 10.1042/BST0380552
ISSN: 0300-5127
Links: http://www.biochemsoctrans.org/content/38/2/552
http://hdl.handle.net/2381/8037
Type: Article
Rights: This is the author's final draft of the paper published as Biochemical Society Transactions, 2010, 38 (2), pp. 552-558. The final version of record is available from http://www.biochemsoctrans.org/content/38/2/552 Doi: 10.1042/BST0380552
Appears in Collections:Published Articles, Dept. of Genetics

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