Trehalose, a Novel mTOR-independent Autophagy Enhancer, Accelerates the Clearance of Mutant Huntingtin and α-Synuclein
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Abstract
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 alpha-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.
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The record
- Venue
- Journal of Biological Chemistry
- Topic
- Autophagy in Disease and Therapy
- Field
- Medicine
- Canadian institutions
- —
- Funders
- Biotechnology and Biological Sciences Research CouncilMedical Research CouncilNational Institutes of HealthInstitute of GeneticsWellcome Trust
- Keywords
- AutophagyHuntingtinTrehaloseChemical chaperoneCell biologyPI3K/AKT/mTOR pathwayActivator (genetics)MutantBAG3BiochemistryHuntingtin ProteinChemistryBiologyAlpha-synucleinApoptosisSignal transductionParkinson's diseaseReceptor
- Has abstract in OpenAlex
- yes