Study Rationale: Our genetic studies of Parkinson’s disease (PD) have found a protective effect of an immune gene called HLA-DR, specifically the presence of the HLA-DRB1*04 subtype. We found that HLA-DRB1*04 binds specifically to a part of alpha-synuclein, the protein enriched in Lewy body aggregates seen in PD brains. We hypothesize that these alpha-synuclein fragments, when bound to HLA- DRB1*04, stimulate immune cells that in turn help clear Lewy body aggregates or prevent their formation. In this study, we investigate how this happens and why individuals with the HLA-DRB1*04 gene are protected from PD. The findings could lead to new immune-based therapies.
Hypothesis: We hypothesize that DRB1*04 binds to a critical part of alpha-synuclein and that this association drives an effective immune response that allows fewer alpha-synuclein aggregates and Lewy bodies to form in the brain.
Study Design: Our immunogenetic analyses will examine 30,000 post-mortem brain samples to examine the HLA-DR subtypes associations in PD, determine whether the age of onset of PD symptoms is associated with DRB1*04 and analyze the association of DRB1*04 with Lewy bodies in PD brain samples and Lewy body disease samples. Our functional immune studies will identify the alpha-synuclein fragments that bind to DRB1*04 and use these fragments to isolate, analyze and compare the alpha-synuclein reactive immune T cells from PD patients and controls.
Impact on Diagnosis/Treatment of Parkinson’s disease: Knowledge of the mechanism of how DRB1*04 mediates protection against PD could be used to slow or stop PD progression. Furthermore, determining the immune correlates of PD protection could be used as a therapeutic biomarker.
Next Steps for Development: Our findings could pave the way for immunotherapies in which alpha-synuclein reactive immune cells or antibodies are us