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Hsp27 reduces glycation-induced toxicity and aggregation of alpha-synuclein

Lookup NU author(s): Professor Tiago Outeiro

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Abstract

© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biologyα-synuclein (aSyn) is a major player in Parkinson's disease and a group of other disorders collectively known as synucleinopathies, but the precise molecular mechanisms involved are still unclear. aSyn, as virtually all proteins, undergoes a series of posttranslational modifications during its lifetime, which can affect its biology and pathobiology. We recently showed that glycation of aSyn by methylglyoxal (MGO) potentiates its oligomerization and toxicity, induces dopaminergic neuronal cell loss in mice, and affects motor performance in flies. Small heat-shock proteins (sHsps) are molecular chaperones that facilitate the folding of proteins or target misfolded proteins for clearance. Importantly, sHsps were shown to prevent aSyn aggregation and cytotoxicity. Upon treating cells with increasing amounts of methylglyoxal, we found that the levels of Hsp27 decreased in a dose-dependent manner. Therefore, we hypothesized that restoring the levels of Hsp27 in glycating environments could alleviate the pathogenicity of aSyn. Consistently, we found that Hsp27 reduced MGO-induced aSyn aggregation in cells, leading to the formation of nontoxic aSyn species. Remarkably, increasing the levels of Hsp27 suppressed the deleterious effects induced by MGO. Our findings suggest that in glycating environments, the levels of Hsp27 are important for modulating the glycation-associated cellular pathologies in synucleinopathies.


Publication metadata

Author(s): Vicente Miranda H, Chegao A, Oliveira MS, Fernandes Gomes B, Enguita FJ, Outeiro TF

Publication type: Article

Publication status: Published

Journal: FASEB Journal

Year: 2020

Pages: epub ahead of print

Online publication date: 07/04/2020

Acceptance date: 12/03/2020

ISSN (print): 0892-6638

ISSN (electronic): 1530-6860

Publisher: John Wiley and Sons Inc.

URL: https://doi.org/10.1096/fj.201902936R

DOI: 10.1096/fj.201902936R


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