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bioRxiv · 10.1101/2020.02.20.956599

T cells limit accumulation of aggregate pathology following intrastriatal injection of α-synuclein fibrils

George, S.·Tyson, T.·Rey, N. L.·Sheridan, R.·Peerlaerts, W.·Becker, K.·Schulz, E.·Meyerdirk, L.·Burmeister, A.·Steiner, J.·Escobar, M. L.·Ma, J.·Brundin, L.·Brundin, P.
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Abstract

Background: -Synuclein (-syn) is the predominant protein in Lewy-body inclusions, which are pathological hallmarks of -synucleinopathies, such as Parkinsons 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 -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 -syn pathology. Methods: We injected human -syn preformed fibrils (PFFs) into the striatum of immunocompromised mice (NSG) and assessed accumulation of phosphorylated -syn pathology, proteinase K-resistant -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 -syn pathology in the substantia nigra. Reconstituting the T cell population decreased the accumulation of phosphorylated -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 -synucleinopathy.

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George, S., Tyson, T., Rey, N. L., Sheridan, R., Peerlaerts, W., Becker, K., Schulz, E., Meyerdirk, L., Burmeister, A., Steiner, J., Escobar, M. L., Ma, J., Brundin, L., Brundin, P.. 2020-02-24. T cells limit accumulation of aggregate pathology following intrastriatal injection of α-synuclein fibrils. https://doi.org/10.1101/2020.02.20.956599

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