Dataset Information

Glycation modulates glutamatergic signaling and exacerbates ParkinsonÃ¢â‚¬â„¢s disease-like phenotypes

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 ParkinsonÃ¢â‚¬â„¢s disease (PD) and, interestingly, a common molecular alteration among these disorders is the age-associated increase in protein glycation. We hypothesized that glycation-induced neuronal dysfunction might be a contributing factor in synucleinopathies. Here, we dissected the specific 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 (ICV) 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. Notably, the glycated proteins in the midbrain of Thy1-aSyn mice that received MGO 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.

INSTRUMENT(S): TripleTOF 6600

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, Regional Part Of Brain

DISEASE(S): Parkinson's Disease

SUBMITTER: Hugo Vicente Miranda

LAB HEAD: Hugo Vicente Miranda

PROVIDER: PXD032832 | Pride | 2022-05-20

REPOSITORIES: Pride

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			Action	DRS
	IDA_Pool_C-A_2uL.wiff	Wiff
	IDA_Pool_C-A_2uL.wiff.scan	Wiff
	IDA_Pool_C-A_8uL_win1.wiff	Wiff
	IDA_Pool_C-A_8uL_win1.wiff.scan	Wiff
	IDA_Pool_C-A_8uL_win2.wiff	Wiff

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

Chegão Ana A Guarda Mariana M Alexandre Bruno M BM Shvachiy Liana L Temido-Ferreira Mariana M Marques-Morgado Inês I Fernandes Gomes Bárbara B Matthiesen Rune R Lopes Luísa V LV Florindo Pedro R PR Gomes Ricardo A RA Gomes-Alves Patrícia P Coelho Joana E JE Outeiro Tiago Fleming TF Vicente Miranda Hugo H

NPJ Parkinson's disease 20220425 1

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 i ...[more]

PMID: 35468899

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