Journal of Biological Chemistry
Volume 282, Issue 8, 23 February 2007, Pages 5641-5652
Journal home page for Journal of Biological Chemistry

Protein Synthesis, Post-Translation Modification, and Degradation
Trehalose, a Novel mTOR-independent Autophagy Enhancer, Accelerates the Clearance of Mutant Huntingtin and α-Synuclein*

https://doi.org/10.1074/jbc.M609532200Get rights and content
Under a Creative Commons license
open access

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 α-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.

Cited by (0)

*

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.