The study investigates the role of microglial reactivity in the propagation of alpha-synuclein (αSyn) and neurodegeneration in a Parkinson's disease (PD) mouse model. Microglial reactivity, induced by co-injection of lipopolysaccharide (LPS) and αSyn preformed fibrils (PFF), was found to exacerbate αSyn accumulation and neurodegeneration compared to PFF injection alone. Oral administration of PLX5622, a microglial inhibitor targeting the colony-stimulating factor 1 receptor (CSF1R), significantly reduced microglial reactivity, decreased αSyn pathology, and alleviated dopaminergic neuron degeneration in the PD mouse model. These findings suggest that microglial inhibition may be a promising therapeutic strategy to mitigate αSyn pathology and neurodegeneration in PD. The study highlights the complex role of microglia in synucleinopathy and the potential of CSF1R inhibitors as a therapeutic target.The study investigates the role of microglial reactivity in the propagation of alpha-synuclein (αSyn) and neurodegeneration in a Parkinson's disease (PD) mouse model. Microglial reactivity, induced by co-injection of lipopolysaccharide (LPS) and αSyn preformed fibrils (PFF), was found to exacerbate αSyn accumulation and neurodegeneration compared to PFF injection alone. Oral administration of PLX5622, a microglial inhibitor targeting the colony-stimulating factor 1 receptor (CSF1R), significantly reduced microglial reactivity, decreased αSyn pathology, and alleviated dopaminergic neuron degeneration in the PD mouse model. These findings suggest that microglial inhibition may be a promising therapeutic strategy to mitigate αSyn pathology and neurodegeneration in PD. The study highlights the complex role of microglia in synucleinopathy and the potential of CSF1R inhibitors as a therapeutic target.