T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease

• DOI: 10.1007/s00401-020-02126-w
• Publication Date: 2020-01-29T01:02:20Z
• Authors: Gregory P. Williams; David J. Marmion; Aubrey M. Schonhoff; Asta Jurkuvenaite; Woong-Jai Won; David G. Standaert; Jeffrey H. Kordower; Ashley S. Harms
• Keywords: Infiltration (HVAC)

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by abnormal accumulation of alpha-synuclein (α-syn) in oligodendrocytes accompanied inflammation, demyelination, and subsequent synapse neuronal loss. Little known about the mechanisms neurodegeneration MSA. However, recent work has highlighted important role immune to pathophysiology other synuclein-related diseases such as Parkinson's disease. In this study, we investigated postmortem brain tissue from MSA patients control subjects for evidence activation brain. We found significant increase HLA-DR+ microglia putamen substantia nigra patient compared controls, well increases CD3+, CD4+, CD8+ T cells these same regions. To model vivo, utilized viral vector that selectively overexpresses α-syn (Olig001-SYN) with > 95% tropism dorsal striatum mice, resulting demyelination neuroinflammation similar observed human Oligodendrocyte transduction resulted robust inflammatory response, which included increased MHCII expression on central nervous (CNS) resident microglia, infiltration pro-inflammatory monocytes into CNS. also CD4 CNS antigen-experienced draining cervical lymph nodes. Importantly, genetic deletion TCR-β or attenuated α-syn-induced inflammation vivo. These results suggest cell priming are key disease pathogenesis MSA, therapeutics targeting may be modifying.