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J. Biol. Chem., Vol. 282, Issue 8, 5641-5652, February 23, 2007

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Trehalose, a Novel mTOR-independent Autophagy Enhancer, Accelerates the Clearance of Mutant Huntingtin and -Synuclein^*

Sovan Sarkar, Janet E. Davies, Zebo Huang¹, Alan Tunnacliffe, and David C. Rubinsztein²

From the Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, United Kingdom and the Institute of Biotechnology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QT, United Kingdom

Trehalose, a disaccharide present in many non-mammalian species, protects cells against various environmental stresses. Whereas some of the protective effects may be explained by its chemical chaperone properties, its actions are largely unknown. Here we report a novel function of trehalose as an mTOR-independent autophagy activator. Trehalose-induced autophagy enhanced the clearance of autophagy substrates like mutant huntingtin and the A30P and A53T mutants of -synuclein, associated with Huntington disease (HD) and Parkinson disease (PD), respectively. Furthermore, trehalose and mTOR inhibition by rapamycin together exerted an additive effect on the clearance of these aggregate-prone proteins because of increased autophagic activity. By inducing autophagy, we showed that trehalose also protects cells against subsequent pro-apoptotic insults via the mitochondrial pathway. The dual protective properties of trehalose (as an inducer of autophagy and chemical chaperone) and the combinatorial strategy with rapamycin may be relevant to the treatment of HD and related diseases, where the mutant proteins are autophagy substrates.

Received for publication, October 10, 2006 , and in revised form, November 22, 2006.

^* This work was supported in part by the Gates Cambridge Scholarship (to S. S.), Wellcome Trust Senior Fellowship in Clinical Science (to D. C. R.), an MRC programme grant, EU Framework VI (EUROSCA) (to D. C. R.), and BBSRC Grant 8/C17391 (to A. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S5.

¹ Current address: College of Pharmacy, Wuhan University, Wuhan 430072, China.

² To whom correspondence should be addressed: Dept. of Medical Genetics, University of Cambridge, Cambridge Inst. for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2XY, United Kingdom. Tel.: 0-1223-762608; Fax: 0-1223-331206; E-mail: dcr1000{at}cam.ac.uk.

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