Alpha-synuclein (aSyn) aggregation in Lewy bodies is a pathological hallmark of Parkinson’s disease (PD) and other synucleinopathies. Glycation, an age-dependent protein modification, is present in Lewy bodies. Here, we investigated the effect of the natural glycating agent methylglyoxal on aSyn biology and found that glycation increased aSyn aggregation and toxicity. Notably, striatal injection of methylglyoxal in mice caused neuronal loss. Genetic and pharmacological manipulation of methylglyoxal increased aSyn‑dependent toxicity in human LUHMES cells and in PD patient-derived iPSCs, and decreased motor performance and survival in aSyn transgenic flies. Furthermore, glycated aSyn impaired synaptic transmission in rat hippocampal slices. Methylglyoxal promoted aSyn oligomerization by affecting its N-terminal structure and impairing lipid-binding ability. Glycation disrupted proteostasis, reducing aSyn turnover, aggregation, and release, likely the mechanistic link underlying the phenotypes observed. In total, our study uncovers glycation as a novel player in synucleinopathies, opening novel avenues for the design of therapeutic strategies.
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