Journal Article

DZNE-2025-01195

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Glycation of alpha-synuclein enhances aggregation and neuroinflammatory responses.

Vasili, E. ; König, A. ; Al-Azzani, M. ; Bosbach, C. ; Gatzemeier, L. M. ; Thom, S. ; Chegão, A. ; Miranda, H. V. ; Steinem, C. ; Erskine, D. ; Outeiro, T. F. (Last author)DZNE*

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41531-025-01159-w

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.

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Contributing Institute(s):

1. Epigenetics and Systems Medicine in Neurodegenerative Diseases (AG Fischer)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2025

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