Humanized mice expressing HLA-DRB1*04:01 show reduced alpha-synuclein aggregation, less dopaminergic axon injury, and lower systemic inflammation compared with HLA-DRB1*04:02, with evidence of an activated microglial state consistent with enhanced alpha-synuclein clearance.

Provides experimental in vivo support that HLA genotype modulates alpha-synuclein pathology, highlighting an immune-genetic mechanism that could inform patient stratification, biomarker development, and immune- or microglia-directed therapeutic strategies for PD.

BACKGROUND AND OBJECTIVE: There is increasing evidence that human leukocyte antigen (HLA) allelic variants play a role in the genetic predisposition to Parkinson disease (PD). In this regard, we have recently reported that the HLA-DRB1*04:01 allele, 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 whether HLA-DRB1*04:01 can modulate PD pathology in vivo. METHODS: We induced the alpha-synuclein preformed fibrils seeding PD model in humanized mice expressing the HLA-DRB1*04:01 or HLA-DRB1*04:02 allele. 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 expressing HLA-DRB1*04:01 display limited alpha-synuclein aggregation and lower dopaminergic axonal injury compared with mice expressing HLA-DRB1*04:02, along with reduced systemic inflammation. We also show that the microglia compartment in HLA-DRB1*04:01 mice 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 the HLA-DRB1*04:01 allele against alpha-synuclein pathology.