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Human Molecular Genetics Advance Access published online on October 6, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm294
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

A rational mechanism for combination treatment of Huntington's disease using lithium and rapamycin

Sovan Sarkar*, Gauri Krishna*,{dagger},{ddagger}, Sara Imarisio*,{dagger},{ddagger}, Shinji Saiki*, Cahir J. O'Kane{dagger} and David C. Rubinsztein*,§

* Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK {dagger} Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK

§ Correspondence to D.C. Rubinsztein - E-mail: dcr1000{at}cam.ac.uk, Tel: (0)1223 762608, Fax: (0)1223 331206

Received August 29, 2007; Revised October 3, 2007; Accepted October 3, 2007

Huntington's disease (HD) is caused by a polyglutamine expansion mutation in the huntingtin protein that confers a toxic gain-of-function and causes the protein to become aggregate-prone. Aggregate-prone proteins are cleared by macroautophagy, and upregulating this process by rapamycin, which inhibits the mammalian target of rapamycin (mTOR), attenuates their toxicity in various HD models. Recently we demonstrated that lithium induces mTOR-independent autophagy by inhibiting inositol monophosphatase (IMPase) and reducing inositol and IP3 levels. Here we show that glycogen synthase kinase-3ß (GSK-3ß), another enzyme inhibited by lithium, has opposite effects. In contrast to IMPase inhibition that enhances autophagy, GSK3ß inhibition attenuates autophagy and mutant huntingtin clearance by activating mTOR. In order to counteract the autophagy inhibitory effects of mTOR activation resulting from lithium treatment, we have used the mTOR inhibitor rapamycin in combination with lithium. This combination enhances macroautophagy by mTOR-independent (IMPase inhibition by lithium) and mTOR-dependent (mTOR inhibition by rapamycin) pathways. We provide proof-of-principle for this rational combination treatment approach in vivo by showing greater protection against neurodegeneration in an HD fly model with TOR inhibition and lithium, or in HD flies treated with rapamycin and lithium, compared to either pathway alone.

{ddagger} Joint second authors


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