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Human Molecular Genetics Advance Access originally published online on September 2, 2005
Human Molecular Genetics 2005 14(20):3003-3011; doi:10.1093/hmg/ddi331
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Lithium rescues toxicity of aggregate-prone proteins in Drosophila by perturbing Wnt pathway

Zdenek Berger1,2, Evangelia K. Ttofi1,2, Claire H. Michel2, Matthieu Y. Pasco2, Sean Tenant2, David C. Rubinsztein1,{dagger} and Cahir J. O'Kane2,*,{dagger}

1Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK and 2Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK

* To whom correspondence should be addressed. Tel: +44 1223333177; Fax: +44 1223333992; Email: c.okane{at}gen.cam.ac.uk

Received July 2, 2005; Revised August 12, 2005; Accepted August 24, 2005

We have previously shown that lithium can protect against the polyglutamine toxicity of the Huntington's disease mutation in cell models. Here, we demonstrate for the first time in vivo that lithium can protect against the toxicity caused by aggregate-prone proteins with either polyglutamine or polyalanine expansions in Drosophila. We also show that these protective effects can be partly accounted for by lithium acting through the Wnt/Wg pathway, as a GSK3ß-specific inhibitor and overexpression of dTCF also mediate protective effects. Our data suggest that lithium deserves serious consideration for further studies as a therapeutic for polyglutamine diseases, particularly as it is an established drug that has been used for several decades for chronic treatment of affective disorders.

{dagger} These authors are joint senior authors.


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