Filip Bäckström, Sweden
Lund University Translational Neurogenetics Unit, Department of Experimental Medical ScienceAuthor Of 1 Presentation
THE MHC CLASS II TRANSACTIVATOR MODULATES SEEDED ALPHA-SYNUCLEIN PATHOLOGY AND IMMUNE CELL PROFILES IN AN IN VIVO RAT MODEL OF PARKINSON'S DISEASE
Abstract
Aims
A pro-inflammatory micro-environment has been suggested to promote abnormal folding, aggregation and spread of alpha-synuclein (asyn) in Parkinson's disease (PD). We have previously shown that levels of the major histocompatibility complex class two transactivator (Mhc2ta) regulate MHCII expression, microglial activation, dopaminergic neurodegeneration and motor impairment upon overexpression of human asyn in rats. The purpose of this study was to determine Mhc2ta effects on seeded asyn pathology, local- and peripheral immune profiles.
Methods
We used a human asyn pre-formed fibril (PFF)-seeded model in VRA4-congenic rats, where normal genetic variation in the VRA4 locus make DA.VRA4 rats express lower Mhc2ta levels than DA. PFFs were injected unilaterally to the striatum two weeks after ipsilateral administration of recombinant adeno-associated vectors carrying human asyn to the substantia nigra. We evaluated motor impairment at 2, 5 and 8 weeks and histology and brain- and peripheral immune cell profiles at baseline, 4 and 8 weeks.
Results
Mhc2ta significantly regulated seeded asyn pathology as well as central and peripheral immune profiles. DA.VRA4 had a wider extent and anatomical distribution of insoluble asyn inclusions, enhanced motor impairment and more dopaminergic neurodegeneration compared to DA rats. DA.VRA4 also displayed higher levels of proinflammatory cytokines in serum and higher CD11b+CD45low cell counts in cell-sorted brain tissue, but a lower MHCII expression per cell compared to DA.
Conclusions
We conclude that Mhc2ta regulates seeded asyn pathology as well as local and peripheral immune profiles in vivo. This makes Mhc2ta a promising therapeutic target for the progressive neuropathology in PD.