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

TLDR

Trehalose, a disaccharide found in many non‑mammalian species, protects cells from environmental stresses, though its mechanisms beyond chemical chaperone activity remain largely unknown. The study demonstrates that trehalose acts as an mTOR‑independent activator of autophagy. Trehalose‑induced autophagy promotes clearance of mutant huntingtin and α‑synuclein (A30P, A53T), works additively with rapamycin, and protects cells from mitochondrial apoptosis, suggesting therapeutic potential for Huntington and Parkinson diseases.

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.