Microglial Melatonin Receptor 1 Degrades Pathological Alpha-Synuclein Through Activating LC3-Associated Phagocytosis
Xiao-Yu Yao1,2, Bing-Er Cao2, Jun-Yi Liu3
1Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Aims:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
Melatonin receptor 1 (MT1) is crucial for microglial cells to clear alpha-synuclein (α-Syn) in Parkinson's disease models. MT1 enhances α-Syn degradation, suggesting its neuroprotective role.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Parkinson's disease (PD) involves Lewy bodies (LBs) composed of alpha-synuclein (α-Syn).
- Microglial cells are key immune responders to misfolded proteins like α-Syn.
- The precise mechanisms and molecular targets for microglial clearance of α-Syn remain unclear.
Purpose of the Study:
- To investigate the role of melatonin receptor 1 (MT1) in microglial clearance of α-Syn.
- To elucidate the molecular pathways regulated by MT1 in microglial phagocytosis.
- To determine the impact of MT1 on α-Syn aggregation in neuronal models.
Main Methods:
- Utilized BV2 cells, primary microglia (wild-type and MT1 knockout mice), and primary cortical neurons.
- Manipulated MT1 expression using RNA interference and lentiviral vectors.
- Induced α-Syn pathology with pre-formed fibrils (PFFs) and analyzed using co-immunoprecipitation, immunofluorescence, Western blot, and qPCR.
Main Results:
- MT1 knockout significantly impaired microglial phagocytosis of particles and fibrillar α-Syn.
- Loss of MT1 receptors in microglia exacerbated α-Syn aggregation in neurons.
- MT1 regulates microglial phagocytic function via the Rubicon-dependent LC3-associated phagocytosis (LAP) pathway.
Conclusions:
- Microglial MT1 plays a neuroprotective role by facilitating α-Syn clearance through the MT1-mediated LAP pathway.
- MT1 emerges as a potential therapeutic target for managing α-Syn-related pathologies in Parkinson's disease.
