Shared Epitope-PositiveAlleles Protect Against Alpha-Synuclein Pathology in a Model of Parkinson Disease.

Abstract

BACKGROUND AND OBJECTIVE: There is increasing evidence that human leukocyte antigen () allelic variants play a role in the genetic predisposition to Parkinson disease (PD). In this regard, we have recently reported that theallele, typified by residues Q/R-K/R-R-A-A at positions 70-74 in the HLA-DRβ1 chain in combination with valine at position 11 (11-V), confers moderate protective effects. In this study, we tested whethercan modulate PD pathology in vivo. METHODS: We induced the alpha-synuclein preformed fibrils seeding PD model in humanized mice expressing theorallele. We then performed a comprehensive histopathologic and molecular characterization of the main disease phenotypes by combining quantitative histopathology, RNA-sequencing, flow cytometry immunophenotyping, and cytokine profiling. RESULTS: Mice expressingdisplay limited alpha-synuclein aggregation and lower dopaminergic axonal injury compared with mice expressing, along with reduced systemic inflammation. We also show that the microglia compartment inmice is in an activated steady state, possibly suggesting their mechanistic involvement in alpha-synuclein clearance. DISCUSSION: Altogether, our findings provide the first experimental evidence of the genetic association between the HLA locus and PD susceptibility and support a neuroprotective function for theallele against alpha-synuclein pathology.