Article Text

Download PDFPDF
Pathogenic mechanisms
A08 Metallothioneins and copper metabolism: candidate therapeutic targets in Huntington's disease
  1. A Wyttenbach1,
  2. S Hands1,
  3. R Mason2,
  4. M U Sajjad1,
  5. F Giorgini2
  1. 1Neuroscience Group, School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton, UK
  2. 2Department of Genetics, University of Leicester, Leicester, UK


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.

  • metallothionein
  • polyglutamine aggregation
  • toxicity
  • copper

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.