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

Hands, Sarah L., Mason, Robert, Umar Sajjad, M., Giorgini, Flaviano and Wyttenbach, Andreas (2010) Metallothioneins and copper metabolism are candidate therapeutic targets in huntington’s disease. Biochemical Society Transactions, 38, 552-558. (doi:10.1042/BST0380552).


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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 yeastmodel 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.

Item Type: Article
Digital Object Identifier (DOI): doi:10.1042/BST0380552
ISSNs: 0300-5127 (print)
1470-8752 (electronic)
Related URLs:
Keywords: copper, huntington's disease, metallothionein, polyglutamine expansion, therapeutic target
Subjects: Q Science > QA Mathematics
Divisions : University Structure - Pre August 2011 > School of Biological Sciences
ePrint ID: 145343
Accepted Date and Publication Date:
Date Deposited: 19 Apr 2010 08:25
Last Modified: 31 Mar 2016 13:20

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