Overexpression of alpha-synuclein (-SYN), a protein which plays an important role in the pathogenesis of Parkinson's disease (PD), triggers microglial activation and adaptive immune responses, and leads to neurodegeneration of dopaminergic (DA) neurons. We hypothesized a link between the humoral adaptive immune response and microglial activation in -SYN induced neurodegeneration. To test this hypothesis, we employed adeno-associated virus serotype 2 (AAV2) to selectively over-express human -SYN in the substantia nigra (SN) of wild-type mice and FcR-/- mice, which lack high-affinity receptors for IgG. We found that in wild-type mice, -SYN induced the expression of NF-B p65 and pro-inflammatory molecules. In FcR-/- mice, NF-B activation was blocked and pro-inflammatory signaling was reduced. Microglial activation was examined using immunohistochemistry for gp91PHOX. At four weeks, microglia were strongly activated in wild-type mice, while microglial activation was attenuated in FcR-/- mice. Dopaminergic neurodegeneration was examined using immunohistochemistry for tyrosine hydroxylase (TH) and unbiased stereology. -SYN overexpression led to the appearance of dysmorphic neurites, and a loss of DA neurons in the SN in wild-type animals, while FcR-/- mice did not exhibit neuritic change and were protected from -SYN-induced neurodegeneration 24 weeks after injection. Our results suggest that the humoral adaptive immune response triggered by excess -SYN plays a causative role in microglial activation through IgG-FcR interaction. This involves NF-B signaling, and leads to DA neurodegeneration. Therefore, blocking either FcR signaling or specific intracellular signal transduction events downstream of FcR-IgG interaction, such as NF-B activation, may be viable therapeutic strategies in PD. © 2010 Cao et al; licensee BioMed Central Ltd.