Microglial low-affinity FcγR mediates the phagocytic elimination of dopaminergic neurons in Parkinsons disease degeneration

Abstract

Microglia-mediated neuroinflammation contributes to dopaminergic (DA) neurodegeneration in Parkinsons disease (PD). It is thought that microglial cells interact with DA neurons of the substantia nigra pars compacta (SNpc), the most vulnerable region in parkinsonian neuropathology, playing a critical role through the process of neuronal loss. However, the specific mechanisms by which microglial reactivity is triggered and exerts such a deleterious effect remains unclear. Experimental models of PD in mice have shown that phagocytosis plays an essential role in the elimination of degenerating neurons, suggesting that blocking this microglial function could be beneficial to preserve remaining DA neurons. In the present work, we pinpoint the role of the Fc{gamma} receptor (Fc{gamma}R) as a potential trigger of microglial phagocytosis in PD. We found that the Fc{gamma}R is overexpressed in the degenerating SNpc in postmortem samples of PD patients, alongside histological indications of phagocytic microglia. Likewise, experimental models of PD also show increased Fc{gamma}R expression, together with evidence of similar phagocytosis events. Most importantly, blocking Fc{gamma}R in vitro, by using neutralizing antibodies, reduced the microglial-mediated elimination of DA cells. High resolution imaging revealed that the Fc{gamma}R is involved in phagocytic synapse formation, and appeared polarized, and segregated to actin-rich protruding cups, when interacting one-on-one towards single target DA cells. Additionally, by inhibiting Fc{gamma}R downstream actin-polymerizing signaling Cdc42, microglia were unable to eliminate DA cells. Finally, experiments in vivo, using an experimental model of PD in mouse, revealed that passive immunotherapy with Fc{gamma}R neutralizing monoclonal antibodies, as well as inhibiting its downstream signaling Cdc42, protect DA neurons from elimination. These results indicate that the Fc{gamma}R may be a critical factor inducing DA neuron phagocytosis in PD and suggest a novel immunotherapeutic strategy targeting microglia to preserve neuronal loss.