The gamma chain subunit of Fc receptors is required for alpha-synuclein-induced pro-inflammatory signaling in microglia

Background: The protein alpha-synuclein (alpha-SYN), which is found in the Lewy bodies of dopamine-producing (DA) neurons in the substantia nigra (SN), has an important role in the pathogenesis of Parkinson's disease (PD). Previous studies have shown that neuroinflammation plays a key role in PD pathogenesis. In an AAV-synuclein mouse model of PD, we have found that over-abundance of alpha-SYN triggers the expression of NF-kappa B p65, and leads to microglial activation and DA neurodegeneration. We also have observed that Fc gamma receptors (Fc gamma R), proteins present on the surface of microglia that bind immunoglobulin G (IgG) and other ligands, are key modulators of alpha-SYN-induced neurodegeneration. Methods: In order to study the role of Fc gamma Rs in the interactions of alpha-SYN and microglia, we treated the primary microglial cultures from wild-type (WT) and Fc gamma R-/- mice with aggregated human alpha-SYN in vitro. Results: Using immunocytochemistry, we found that alpha-SYN was taken up by both WT and Fc gamma R-/- microglia, however, their patterns of internalization were different, with aggregation in autophagosomes in WT cells and more diffuse localization in Fc gamma R-/- microglia. In WT microglia, alpha-SYN induced the nuclear accumulation of NF-kappa B p65 protein and downstream chemokine expression while in Fc gamma R-/- mouse microglia, alpha-SYN failed to trigger the enhancement of nuclear NF-kappa B p65, and the pro-inflammatory signaling was reduced. Conclusions: Our results suggest that alpha-SYN can interact directly with microglia and can be internalized and trafficked to autophagosomes. Fc gamma Rs mediate this interaction, and in the absence of the gamma chain, there is altered intracellular trafficking and attenuation of pro-inflammatory NF-kappa B signaling. Therefore, blocking either Fc gamma R signaling or downstream NF-kappa B activation may be viable therapeutic strategies in PD.