Inhibition of formation of alpha-synuclein inclusions by mannosylglycerate in a yeast model of Parkinson's disease

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Abstract

Background: Protein aggregation in the brain is a central hallmark in many neurodegenerative diseases. In Parkinson's disease, alpha-synuclein (alpha-Syn) is the major component of the intraneuronal inclusions found in the brains of patients. Current therapeutics is merely symptomatic, and there is a pressing need for developing novel therapies. Previously we showed that mannosylglycerate (MG), a compatible solute typical of marine microorganisms thriving in hot environments, is highly effective in protecting a variety of model proteins against thermal denaturation and aggregation in vitro. Methods: Saccharomyces cerevisiae cells expressing eGFP-tagged alpha-Syn, were further engineered to synthesize MG. The number of cells with fluorescent foci was assessed by fluorescence microscopy. Fluorescence spectroscopy and transmission electron microscopy were used to monitor fibril formation in vitro. Results: We observed a 3.3-fold reduction in the number of cells with alpha-Syn foci and mild attenuation of alpha-Syn-induced toxicity. Accordingly, sucrose gradient analysis confirmed a clear reduction in the size-range of alpha-Syn species in the cells. MG did not affect the expression levels of alpha-Syn or its degradation rate. Moreover, MG did not induce molecular chaperones (Hsp104, Hsp70 and Hsp40), suggesting the implication of other mechanisms for alpha-Syn stabilization. MG also inhibited alpha-Syn fibrillation in vitro. Conclusions: MG acts as a chemical chaperone and the stabilization mechanism involves direct solute/protein interactions. General significance: This is the first demonstration of the anti-aggregating ability of MG in the intracellular milieu. The work shows that MG is a good candidate to inspire the development of new drugs for protein-misfolding diseases. (c) 2013 Elsevier B.V. All rights reserved.
Original languageUnknown
Pages (from-to)4065-4072
JournalBiochimica Et Biophysica Acta-General Subjects
Volume1830
Issue number8
DOIs
Publication statusPublished - 1 Jan 2013

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