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Immune changes in the brain and periphery in Parkinson’s disease (PD) patients have been documented, but how the central and the peripheral immune system impact disease progression is yet unknown. Alpha-synuclein (α-syn) pathological aggregates are the main component of Lewy bodies, the pathological hallmark of PD. Misfolded α-syn can act as a pro-inflammagen and initiate an inflammatory response on both peripheral and central myeloid cells, ultimately inducing both innate and adaptive immune responses. However, our current comprehension of the different immune cell types involved in the disease progression remains elusive. We aim to identify and describe new immune subtypes involved in the α-syn-induced inflammation in the brain and periphery using state-of-the-art techniques such as Single-cell RNA sequencing (scRNAseq). To do so, we have injected mouse α-syn pre-formed fibrils (PFF), monomeric α-syn or PBS into the striatum of male and female rats and performed scRNAseq on total brain cells 2- and 6-months post-injection. In parallel, blood and spleens were collected for evaluation of peripheral immune alterations. Bioinformatic analysis and validation is currently ongoing. Preliminary data show that the α-syn PFF-injected animals had an expansion of the responsive microglia, together with a macrophage and T-cell response. The immune events were sex specific. In addition, the injection of monomeric α-syn resulted in long lasting immune changes that differed from the PFF α-syn but also from the PBS control group. Immunohistochemical analysis has revealed enhanced phosphorylated α-syn pathology in PFF-injected animals after 2 months, resulting in significant dopaminergic neurodegeneration after 6 months. With the ongoing analysis, we expect to uncover disease-related immune changes in the brain critical for disease progression that might also explain the sex dimorphism seen in PD.