Microglial low-affinity FcγR mediates the phagocytic elimination of dopaminergic neurons in Parkinson’s disease degeneration

It is postulated that microglial cells interact with dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc), playing a critical role in Parkinson's disease (PD) neurodegeneration. However, the specific mechanisms by which microglial reactivity is triggered remain unclear. Experimental models of PD in mice indicate that phagocytosis drives the elimination of degenerating neurons, suggesting that blocking this microglial function could preserve remaining DA neurons. Here, we pinpoint the role of Fcγ receptor (FcγR) as a potential trigger of microglial phagocytosis in PD. We found that FcγR is overexpressed in the SNpc of PD patients, alongside indications of phagocytic microglia. Likewise, experimental models of PD show equivalent results. Importantly, blocking FcγR in vivo and in vitro, with neutralizing antibodies, reduced the microglial-mediated elimination of DA cells. These results highlight FcγR as a critical factor inducing DA neuron phagocytosis in PD and suggest a novel immunotherapeutic strategy to prevent neuronal loss.