Summary Genetic variation is an important determinant of Parkinson's disease (PD) risk and progression. Advances in genomic technologies coupled with access to large DNA collections have set in place the foundation to fully describe the genetic component of PD pathogenesis. However, genetic research will fall short of its potential to improve patients' outcomes until we identify the mechanisms underlying the statistical associations. The focus of this proposal is to explore the biology of HLA-mediated susceptibility in PD using genetic, immunological, and computational approaches. We hypothesize that a specific combination of amino acids at positions 70-74 on the α-helix of the HLA-DRβ1 molecule, defining the sides of the HLA peptide-binding groove, drives disease risk or protection through specific adaptive immune responses. We also hypothesize that HLA-cell surface calreticulin interactions in the CNS modulate microglia scavenging activity and neuronal survival. Our preliminary data suggest that these alternative hypotheses are not necessarily in conflict. To address our goals, we will merge genetic and experimental datasets representing PD susceptibility and pathological hallmarks, bringing together expertise in genomics, proteomics, molecular modelling and cellular neurobiology. Specific Aim 1 describes at high resolution the HLA genetic variation associated with PD in non-European datasets, and characterizes the molecular mechanisms underlying the association at both, functional and structural levels. Specific Aim 2 explores the hypothesis that HLA contribution to PD is independent from classic antigen-presentation processes, and rather functions via surface calreticulin- mediated signaling. Lastly, in Specific Aim 3, we will generate the first humanized PD mouse model overexpressing wildtype α-synuclein and carrying a protective HLA allele in order to dissect the influence of this locus on PD phenotypes in a complex in vivo biological environment. Altogether, the proposed aims hold the power to substantially advance the current understanding of PD pathogenesis, with lessons for other neurodegenerative diseases, including the related synucleinopathy Lewy body dementia (LBD).