Methylglyoxal Aggregates α-Synuclein by Inhibiting SIRT1-Hif-1α in Intestinal Enteroendocrine Cells

초록

Parkinson's disease (PD) is characterized by the abnormal aggregation of alpha-synuclein, which can originate in the gut and propagate to the brain. Recent evidence suggests a correlation between metabolic disorders, particularly diabetes, and PD pathogenesis through the gut-brain axis. Methylglyoxal (MGO), a glucose-derived metabolite produced by gut bacteria such as Proteus mirabilis, is implicated in protein misfolding and glycation. This study investigated whether MGO induced alpha-synuclein aggregation in intestinal enteroendocrine cells and explored the underlying mechanisms. Mouse enteroendocrine STC-1 cells were treated with MGO (0.01-1 mM) for 36 h, and changes in alpha-synuclein aggregation, neuronal markers, and relevant signaling pathways were assessed. MGO at 1 mM significantly reduced cell viability and neuronal marker expression, and concentrations of 0.1 and 1 mM increased alpha-synuclein aggregation. MGO also inhibited SIRT1 expression, leading to increased Hif-1 alpha transcription and reduced expression of autophagy-related proteins Beclin1 and LC3B. These changes were accompanied by mitochondrial dysfunction, as evidenced by decreased Bcl2, increased cytochrome C expression, and reduced levels of the antioxidant factor HO-1. Our findings provide the first evidence that MGO directly induces alpha-synuclein aggregation in enteroendocrine cells via the SIRT1-Hif-1 alpha-autophagy pathway dysregulation, establishing a potential mechanistic link between gut microbiome-derived metabolites and PD pathogenesis. These results suggest that intestinal glycation may be a critical target for preventing alpha-synuclein pathology originating in the gut.

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