Journal Article

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

Sovan Sarkar, Gauri Krishna, Sara Imarisio, Shinji Saiki, Cahir J. O'Kane and David C. Rubinsztein

in Human Molecular Genetics

Volume 17, issue 2, pages 170-178
Published in print January 2008 | ISSN: 0964-6906
Published online October 2007 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddm294
A rational mechanism for combination treatment of Huntington's disease using lithium and rapamycin

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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-3β (GSK-3β), another enzyme inhibited by lithium, has opposite effects. In contrast to IMPase inhibition that enhances autophagy, GSK3β 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 with either pathway alone.

Journal Article.  5412 words.  Illustrated.

Subjects: Genetics and Genomics

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