NeuralCipher Research overview
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BackgroundParkinson's disease (PD), a common neurodegenerative condition, afflicts patients through the progressive degeneration of dopaminergic neurons and sustained neuroinflammation. This study investigates the role of olfactory mucosa-derived mesenchymal stem cell (OM-MSC)-derived exosomes, particularly the long non-coding RNA A2M-AS1 (lncA2M-AS1), in modulating microglial metabolism reprogramming and neuroinflammation in PD.MethodsA mouse PD model was established using MPTP injections. Animals received treatments including OM-MSC-derived exosomes knockdown for lncA2M-AS1 or AAV-mediated lncA2M-AS1 overexpression. Motor function was assessed using the open field test and the apomorphine-induced rotation test. Glycolytic metabolism was evaluated by measuring ECAR and OCR using Seahorse XFp Analyzer, and the expression of glycolytic proteins (GLUT1, HK2, PKM2, LDHA) via Western blot. Molecular analyses included qPCR, Western blot, Co-IP, and ubiquitination assays that were performed to investigate the lncA2M-AS1/CFL1/ROCK1 regulatory axis. Histological examinations involved immunohistochemistry for TH and IBA1. The expressions of lncA2M-AS1 and ROCK1 were determined in serum obtained from individuals with PD and matched controls.ResultsLncA2M-AS1 is downregulated in PD patient serum and MPTP mice. OM-MSC exosomal lncA2M-AS1 suppressed microglial glycolysis, reduced pro-inflammatory cytokine release, enhanced neuronal viability, and improved motor function in PD mice. Mechanistically, lncA2M-AS1 directly binds to CFL1 mRNA, promoting ubiquitin-mediated degradation of ROCK1 and inhibiting the CFL1/ROCK1 pathway. Knockdown of CFL1 or overexpression of lncA2M-AS1 attenuated microglial activation and neuroinflammation, whereas ROCK1 overexpression reversed these protective effects.ConclusionOM-MSC exosomal lncA2M-AS1 ameliorates PD pathogenesis by targeting the CFL1/ROCK1 axis to reprogram microglial glucose metabolism and suppress neuroinflammation, offering a novel therapeutic strategy for PD.
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