Phagocytic macrophages mitigate α-Synuclein pathology in an astrocyte-driven model of neurodegeneration

Parkinson’s disease (PD), a chronic and progressive neurodegenerative disorder, has long been studied from a neuron-centric perspective. However, more recent research indicates that neuroinflammation plays a key role in the pathological process, shifting the focus toward non- neuronal cells such as astrocytes, which are no longer seen as mere passive bystanders. In this study, we investigated the role of α-Synuclein (αSYN) accumulation in astrocytes as a trigger of neurodegeneration and immune responses in PD, isolating and examining the specific consequences of astrocytic pathology in the absence of direct neuronal αSYN expression. Our results demonstrate that astrocyte-specific αSYN accumulation is sufficient to induce significant dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), accompanied by strong glial activation and widespread recruitment of peripheral immune cells into the brain parenchyma. Transcriptomic analysis revealed a pro-inflammatory profile, characterized by increased expression of chemokines and immune-related signalling pathways, suggesting that astrocytes actively participate in shaping the neuroimmune environment. To determine whether these effects depend on the presence of microglia, we chronically depleted microglial cells using the PLX3397 compound. Surprisingly, T cell infiltration persisted even in the absence of microglia, providing strong evidence that astrocytes are capable of orchestrating peripheral immune recruitment. Interestingly, microglia depletion also led to a reduction in αSYN aggregate burden, suggesting a complex and potentially dual role of microglia in both the clearance and maintenance of protein pathology. Single-cell RNA sequencing of CD45+ immune cells from the striatum (STR) revealed a novel macrophage subpopulation with high phagocytic activity, alongside immunologically “exhausted” lymphocytes. This co-occurrence indicates a shift toward a tolerogenic, clearance-oriented immune state in the context of microglial depletion. Our findings demonstrate that astrocytic αSYN is not merely a byproduct of pathology but a key driver of neurodegeneration and neuroinflammation. Astrocytes actively recruit immune cells and reshape the brain’s immune landscape. In the absence of microglia, a distinct population of phagocytic macrophages emerges as powerful clean-up cells, opening new avenues to enhance proteostasis and restrain inflammation. Together with the central role of astrocytes in PD–associated neurodegeneration, these findings point to novel strategies for protecting dopaminergic neurons and restoring neuroimmune balance.