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Microglial Melatonin Receptor 1 Degrades Pathological Alpha-Synuclein Through Activating LC3-Associated Phagocytosis In Vitro

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机构： [1]Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China. [2]Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China. [3]Department of Neurology, The Fourth Affiliated Hospital of Soochow University, Suzhou, China. [4]Department of Neurology, Xiongan Xuanwu Hospital, Xiongan, China.

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关键词： LC3-associated phagocytosis melatonin receptor 1 microglia Parkinson's disease α-synuclein

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Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs), primarily constituted of α-synuclein (α-Syn). Microglial cells exhibit specific reactivity toward misfolded proteins such as α-Syn. However, the exact clearance mechanism and related molecular targets remain elusive.BV2 cells, primary microglia from wild-type and MT1 knockout mice, and primary cortical neurons were utilized as experimental models. The study investigated relevant mechanisms by modulating microglial MT1 expression through small RNA interference (RNAi) and lentiviral overexpression techniques. Furthermore, pathological aggregation of α-Syn was induced using pre-formed fibrils (PFF) α-Syn. Co-immunoprecipitation, immunofluorescence, Western blot (WB), and quantitative real-time PCR were used to elucidate the mechanisms of molecular regulation.In this study, we elucidated the regulatory role of the melatonin receptor 1 (MT1) in the microglial phagocytic process. Following MT1 knockout, the ability of microglial cells to engulf latex beads and zymosan particles decreased, subsequently affecting the phagocytic degradation of fibrillar α-Syn by microglial cells. Furthermore, the loss of MT1 receptors in microglial cells exacerbates the aggregation of α-Syn in neurons induced by pre-formed fibrils (PFF) α-Syn. Mechanistically, MT1 influences the phagocytic function of microglial cells by regulating the Rubicon-dependent LC3-associated phagocytosis (LAP) pathway.Taken together, the results suggest the neuroprotective function of microglial cells in clearing α-Syn through MT1-mediated LAP, highlighting the potential key role of MT1 in pathogenic mechanisms associated with α-Syn.© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.

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出版当年[2023]版：

大类 | 1 区医学

小类 | 2 区神经科学 2 区药学

最新[2023]版：

大类 | 1 区医学

小类 | 2 区神经科学 2 区药学

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出版当年[2022]版：

Q1 NEUROSCIENCES Q1 PHARMACOLOGY & PHARMACY

最新[2023]版：

Q1 PHARMACOLOGY & PHARMACY Q1 NEUROSCIENCES

影响因子： 4.8 最新[2023版] 5.9 最新五年平均 5.5 出版当年[2022版] 6.2 出版当年五年平均 7.035 出版前一年[2021版] 4.8 出版后一年[2023版]

第一作者：

第一作者机构： [1]Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China. [2]Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China.

通讯作者：

通讯机构： [1]Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China. [2]Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China. [4]Department of Neurology, Xiongan Xuanwu Hospital, Xiongan, China.

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