T Cells Limit Accumulation Of Aggregate Pathology Following Intrastriatal Injection Of Alpha-Synuclein Fibrils

Background: alpha-Synuclein (alpha-syn) is the predominant protein in Lewy-body inclusions, which are pathological hallmarks of alpha-synucleinopathies, such as Parkinson's disease (PD) and multiple system atrophy (MSA). Other hallmarks include activation of microglia, elevation of pro-inflammatory cytokines, as well as the activation of T and B cells. These immune changes point towards a dysregulation of both the innate and the adaptive immune system. T cells have been shown to recognize epitopes derived from alpha-syn and altered populations of T cells have been found in PD and MSA patients, providing evidence that these cells can be key to the pathogenesis of the disease.Objective To study the role of the adaptive immune system with respect to alpha-syn pathology.Methods: We injected human alpha-syn preformed fibrils (PFFs) into the striatum of immunocompromised mice (NSG) and assessed accumulation of phosphorylated alpha-syn pathology, proteinase K-resistant alpha-syn pathology and microgliosis in the striatum, substantia nigra and frontal cortex. We also assessed the impact of adoptive transfer of naive T and B cells into PFF-injected immunocompromised mice.Results: Compared to wildtype mice, NSG mice had an 8-fold increase in phosphorylated alpha-syn pathology in the substantia nigra. Reconstituting the T cell population decreased the accumulation of phosphorylated alpha-syn pathology and resulted in persistent microgliosis in the striatum when compared to non-transplanted mice.Conclusion: Our work provides evidence that T cells play a role in the pathogenesis of experimental alpha-synucleinopathy.