Author(s): Vasili, Eftychia ; König, Annekatrin ; Al-Azzani, Mohammed ; Bosbach, Clara ; Gatzemeier, Luisa Maria ; Thom, Searlait ; Chegão, Ana ; Vicente Miranda, Hugo ; Steinem, Claudia ; Erskine, Daniel ; Outeiro, Tiago Fleming
Date: 2025
Persistent ID: http://hdl.handle.net/10362/191007
Origin: Repositório Institucional da UNL
Subject(s): Neurology; Clinical Neurology; Cellular and Molecular Neuroscience; SDG 3 - Good Health and Well-being
Publisher Copyright: © The Author(s) 2025.
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.
