Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes

2022 | journal article; research paper. A publication with affiliation to the University of Göttingen.

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​Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes​
Chegão, A.; Guarda, M.; Alexandre, B. M.; Shvachiy, L.; Temido-Ferreira, M.; Marques-Morgado, I. & Fernandes Gomes, B. et al.​ (2022) 
npj Parkinson's Disease8(1) art. 51​.​ DOI: https://doi.org/10.1038/s41531-022-00314-x 

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Authors
Chegão, Ana; Guarda, Mariana; Alexandre, Bruno M.; Shvachiy, Liana; Temido-Ferreira, Mariana; Marques-Morgado, Inês; Fernandes Gomes, Bárbara; Matthiesen, Rune; Lopes, Luísa V.; Florindo, Pedro R.; Vicente Miranda, Hugo
Abstract
Abstract Alpha-synuclein (aSyn) is a central player in the pathogenesis of synucleinopathies due to its accumulation in typical protein aggregates in the brain. However, it is still unclear how it contributes to neurodegeneration. Type-2 diabetes mellitus is a risk factor for Parkinson’s disease (PD). Interestingly, a common molecular alteration among these disorders is the age-associated increase in protein glycation. We hypothesized that glycation-induced neuronal dysfunction is a contributing factor in synucleinopathies. Here, we dissected the impact of methylglyoxal (MGO, a glycating agent) in mice overexpressing aSyn in the brain. We found that MGO-glycation potentiates motor, cognitive, olfactory, and colonic dysfunction in aSyn transgenic (Thy1-aSyn) mice that received a single dose of MGO via intracerebroventricular injection. aSyn accumulates in the midbrain, striatum, and prefrontal cortex, and protein glycation is increased in the cerebellum and midbrain. SWATH mass spectrometry analysis, used to quantify changes in the brain proteome, revealed that MGO mainly increase glutamatergic-associated proteins in the midbrain (NMDA, AMPA, glutaminase, VGLUT and EAAT1), but not in the prefrontal cortex, where it mainly affects the electron transport chain. The glycated proteins in the midbrain of MGO-injected Thy1-aSyn mice strongly correlate with PD and dopaminergic pathways. Overall, we demonstrated that MGO-induced glycation accelerates PD-like sensorimotor and cognitive alterations and suggest that the increase of glutamatergic signaling may underly these events. Our study sheds new light into the enhanced vulnerability of the midbrain in PD-related synaptic dysfunction and suggests that glycation suppressors and anti-glutamatergic drugs may hold promise as disease-modifying therapies for synucleinopathies.
Issue Date
2022
Journal
npj Parkinson's Disease 
Project
EXC 2067: Multiscale Bioimaging 
SFB 1286: Quantitative Synaptologie 
SFB 1286 | B08: Definition von Kaskaden molekularer Veränderungen bei Synucleinopathien während der Neurodegeneration 
Working Group
RG Outeiro (Experimental Neurodegeneration) 
External URL
https://mbexc.uni-goettingen.de/literature/publications/539
https://sfb1286.uni-goettingen.de/literature/publications/173
eISSN
2373-8057
Language
English

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