Microglial inhibition alleviates alpha-synuclein (aSyn) propagation and neurodegeneration in Parkinson’s disease (PD) mouse models. The study investigated the role of microglial reactivity in PD pathogenesis, focusing on its contribution to aSyn accumulation and neurodegeneration. Using a PD mouse model injected with preformed aSyn fibrils (PFF), researchers co-injected lipopolysaccharide (LPS) to induce microglial activation and examined the effects of microglial inhibition with PLX5622, a CSF1R inhibitor. Results showed that LPS injection increased microglial reactivity, aSyn accumulation, and neurodegeneration compared to PFF injection alone. However, treatment with PLX5622 significantly reduced microglial reactivity, aSyn pathology, and dopaminergic neuron degeneration. These findings suggest that microglial reactivity exacerbates aSyn propagation and neurodegeneration in PD, and that microglial inhibition may be a promising therapeutic strategy to slow disease progression. The study also demonstrated that microglial reactivity is a key contributor to synucleinopathy, with microglia playing both protective and harmful roles in aSyn pathology and neurodegeneration. Microglial inhibition reduced aSyn accumulation and neurodegeneration, as well as motor deficits, in PD mouse models. These results highlight the potential of microglial targeting as a therapeutic approach for PD. Further research is needed to fully understand the molecular mechanisms and long-term effects of microglial inhibition in synucleinopathy and neurodegeneration.Microglial inhibition alleviates alpha-synuclein (aSyn) propagation and neurodegeneration in Parkinson’s disease (PD) mouse models. The study investigated the role of microglial reactivity in PD pathogenesis, focusing on its contribution to aSyn accumulation and neurodegeneration. Using a PD mouse model injected with preformed aSyn fibrils (PFF), researchers co-injected lipopolysaccharide (LPS) to induce microglial activation and examined the effects of microglial inhibition with PLX5622, a CSF1R inhibitor. Results showed that LPS injection increased microglial reactivity, aSyn accumulation, and neurodegeneration compared to PFF injection alone. However, treatment with PLX5622 significantly reduced microglial reactivity, aSyn pathology, and dopaminergic neuron degeneration. These findings suggest that microglial reactivity exacerbates aSyn propagation and neurodegeneration in PD, and that microglial inhibition may be a promising therapeutic strategy to slow disease progression. The study also demonstrated that microglial reactivity is a key contributor to synucleinopathy, with microglia playing both protective and harmful roles in aSyn pathology and neurodegeneration. Microglial inhibition reduced aSyn accumulation and neurodegeneration, as well as motor deficits, in PD mouse models. These results highlight the potential of microglial targeting as a therapeutic approach for PD. Further research is needed to fully understand the molecular mechanisms and long-term effects of microglial inhibition in synucleinopathy and neurodegeneration.