The MHC class II transactivator modulates seeded alpha-synuclein pathology and dopaminergic neurodegeneration in an in vivo rat model of Parkinson's disease

Background: Abnormal folding, aggregation and spreading of alpha-synuclein (alpha syn) is a mechanistic hypothesis for the progressive neuropathology in Parkinson's disease (PD). Spread of alpha syn between cells is supported by clinical, neuropathological and experimental evidence. It has been proposed that a pro-inflammatory micro environment in response to alpha syn can promote its aggregation. We have previously shown that allelic differences in the major histocompatibility complex class two transactivator (Mhc2ta) gene, located in the VRA4 locus, alter MHCII expression levels, microglial activation and antigen presentation capacity in rats upon human alpha syn over expression. In addition, Mhc2ta regulated dopaminergic neurodegeneration and the extent of motor impairment. The purpose of this study was to determine whether Mhc2ta regulates alpha syn aggregation, propagation and dopaminergic pathology in an alpha syn pre-formed fibril (PFF)-seeded in vivo model of PD. Methods: The DA and DA.VRA4 congenic rat strains share background genome but display differential microglial antigen presenting capacity due to different Mhc2ta alleles in the VRA4 locus. PFFs of human alpha syn or BSA solution were injected unilaterally to the striatum of DA and DA.VRA4 rats two weeks after ipsilateral administration of recombinant adeno-associated virus (rAAV) vectors carrying human alpha syn or GFP to the substantia nigra pars compacta. Behavioural assessment was performed at 2, 5 and 8 weeks while histological evaluation of alpha syn pathology, inflammation and neurodegeneration as well as determination of serum cytokine profiles were performed at 8 weeks. Results: rAAV-mediated expression of human alpha syn in nigral dopaminergic neurons combined with striatal PFF administration induced enhanced alpha syn pathology in DA.VRA4 compared to DA rats. Mhc2ta thus significantly regulated the seeding, propagation and toxicity of alpha syn in vivo. This was reflected in terms of wider extent and anatomical distribution of alpha syn inclusions, ranging from striatum to the forebrain, midbrain, hindbrain and cerebellum in DA.VRA4. Compared to DA rats, DA.VRA4 also displayed enhanced motor impairment and dopaminergic neurodegeneration as well as higher levels of the proinflammatory cytokines IL-2 and TNF alpha in serum. Conclusions: We conclude that the key regulator of MHCII expression, Mhc2ta, modulates neuroinflammation, alpha syn-seeded Lewy-like pathology, dopaminergic neurodegeneration and motor impairment. This makes Mhc2ta and microglial antigen presentation promising therapeutic targets for reducing the progressive neuropathology and clinical manifestations in PD.