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

Abstract

α-synuclein (aSyn) is a major player in Parkinson's disease (PD) 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 (PTMs) 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 non-toxic 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.

Heat Shock Response and Heat Shock Proteins: Current Understanding and Future Opportunities in Human Diseases

“…Studies have demonstrated the colocalization of HSP27 with αsynuclein in amyloid fibrils, implicating its involvement in PD pathology. The levels of HSP27 are vital for modulating glycation-associated cellular pathologies in synucleinopathies via its binding and inhibition of amyloid nucleation, fibril binding, and fibril disaggregation [272,273]. As an important regulator of cell survival and its role in different cellular functions in normal and stressful conditions, HSP27 is now considered as an important therapeutic target and biomarker in various human diseases.…”