Authors
Vasili E, König A, Al-Azzani M, Bosbach C, Gatzemeier LM, Thom S, Chegão A, Miranda HV, Steinem C, Erskine D, Outeiro TF
Journal
NPJ Parkinsons Disease
Citation
NPJ Parkinsons Dis. 2025 Oct 23;11(1):307.
Abstract
The risk of developing Parkinson’s disease (PD) is elevated in individuals with type 2 diabetes (T2DM), but the molecular pathways underlying this link remain unclear. Glycation, a non-enzymatic modification of lysine and arginine residues by reducing sugars or reactive dicarbonyls, may disrupt proteostasis and trigger pathology. Here, we investigated how methylglyoxal (MGO)- and ribose-mediated glycation influence aSyn aggregation, neuroinflammation, and detoxification pathways. Using SH-SY5Y cells, primary neurons, primary microglia and MGO-injected aSyn transgenic mice, we found that MGO-glycated aSyn promotes PD associated pathological features, including pS129-positive aSyn aggregates, neuroinflammation, and impairment of the glyoxalase detoxification pathway. Ribose-glycated aSyn, while immunogenic, exerts limited effects on aggregation and seeding. Both glycated species activates microglia and upregulate pro-inflammatory markers. We further developed a novel antibody specific for MGO-glycated aSyn, which selectively detects Lewy body-like deposits in dementia with Lewy bodies (DLB) tissue and MGO-injected mice. These findings implicate MGO-glycation in PD-T2DM comorbidity.
