Objective: To explore the effects of microglial myocyte enhancer factor 2C (MEF2C) in neuroinflammation induced by α-synuclein.

Background: The abnormal aggregation of α-synuclein (α-syn) is a critical pathological basis of Parkinson’s disease (PD). Excessive deposition of α-syn can trigger a pro-inflammatory response in microglia, mediating pathological spreading and neural degeneration. MEF2C, acting as an important neuroinflammatory “off” factor, plays a significant regulatory role in the process of neuron apoptosis.

Method: Cerebrospinal fluid (CSF) from PD patients was collected for microarray analysis. C57/BL6 mice and Human Microglial Cells (HMC3) were treated with α-syn (animals: 5 μg for 6 months; cells: 25μmol/L for 24 hours). Lentivirus was used to construct HMC3 cell models with MEF2C overexpression and knockdown (MEF2C-UP and MEF2C-KD). A co-culture system of HMC3 cells and SH-SY5Y cells was established. The mouse brain samples were used for immunohistochemistry and immunofluorescence assays. In vitro cells were analyzed using flow cytometry, PCR, WB, and ELISA to detect apoptosis rates, inflammatory cytokines, and apoptosis-related molecules. RNA antisense purification (RAP) and mass spectrometry were employed to identify regulatory proteins bound to MEF2C mRNA.

Results: Microarray analysis from patients, as well as results from in vivo and in vitro models, consistently demonstrated that the expression of MEF2C is downregulated in PD models. In HMC3 cells, compared to the control cells, the α-syn-treated cells and the MEF2C-KD cells exhibited increased apoptosis rates, elevated secretion of IL-17, IL-12p40, and IL-12p70, and an increased expression of Bax/Bcl-2 and cleaved caspase-3. SH-SY5Y cells co-cultured with these HMC3 cells also showed increased apoptosis rates, along with elevated expression levels of cleaved caspase-3 and p-RIPK1. RNA antisense purification (RAP) confirmed that nucleolin (NCL) and nucleophosmin (NPM1) bind to MEF2C mRNA. Furthermore, the suppression of NCL and NPM1 in microglia also promoted the aforementioned changes in neurons.

Conclusion: The present study reveals α-synuclein may modulate the expression of nucleolar proteins (NCL and NPM1) to suppress MEF2C, driving microglial neuroinflammation and causing neural damage and dysfunction.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/%ce%b1-synuclein-triggers-neuroinflammatory-damage-through-the-suppression-of-mef2c/