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

被引:21
作者
Miranda, Hugo Vicente [1 ]
Chegao, Ana [1 ]
Oliveira, Marcia S. [1 ]
Gomes, Barbara Fernandes [1 ]
Enguita, Francisco J. [2 ]
Outeiro, Tiago Fleming [1 ,3 ,4 ,5 ]
机构
[1] Univ Nova Lisboa, Fac Ciencias Med, Chron Dis Res Ctr, NOVA Med Sch,CEDOC, Lisbon, Portugal
[2] Univ Lisbon, Fac Med, Inst Med Mol Joao Lobo Antunes, Lisbon, Portugal
[3] Univ Med Ctr Gottingen, Ctr Biostruct Imaging Neurodegenerat, Dept Expt Neurodegenerat, Gottingen, Germany
[4] Max Planck Inst Expt Med, Gottingen, Germany
[5] Newcastle Univ, Fac Med Sci, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England
关键词
alpha-synuclein; glycation; Hsp27; neurodegeneration; Parkinson's disease; HEAT-SHOCK PROTEINS; B-CRYSTALLIN; PARKINSONS-DISEASE; NEURODEGENERATIVE DISORDERS; MOLECULAR CHAPERONES; ALZHEIMERS-DISEASE; CELL-DEATH; METHYLGLYOXAL; HEAT-SHOCK-PROTEIN-27; PHOSPHORYLATION;
D O I
10.1096/fj.201902936R
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
alpha-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.
引用
收藏
页码:6718 / 6728
页数:11
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