%0 Journal Article
%A Vasili, Eftychia
%A König, Annekatrin
%A Al-Azzani, Mohammed
%A Bosbach, Clara
%A Gatzemeier, Luisa Maria
%A Thom, Searlait
%A Chegão, Ana
%A Miranda, Hugo Vicente
%A Steinem, Claudia
%A Erskine, Daniel
%A Outeiro, Tiago F
%T Glycation of alpha-synuclein enhances aggregation and neuroinflammatory responses.
%J npj Parkinson's Disease
%V 11
%N 1
%@ 2373-8057
%C [London]
%I Springer Nature
%M DZNE-2025-01195
%P 307
%D 2025
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41131060
%R 10.1038/s41531-025-01159-w
%U https://pub.dzne.de/record/281812