Extracellular transportation of a-synuclein by HLA class II molecules

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of a-synuclein aggregates in form of Lewy bodies. Genome-wide association studies have revealed that human leukocyte antigen (HLA) class II is a PD-associated gene, although the mechanisms linking HLA class II and PD remain elusive. Here, we identified a novel function of HLA class II in the transport of intracellular a-synuclein to the outside of cells. HLA class II molecules and a-synuclein formed complexes and moved to the cell surface at various degrees among HLA-DR alleles. HLA-DR with a DRB5*01:01 allele, a putative PD-risk allele, substantially translocated normal and conformationally abnormal a-synuclein to the cell surface and extracellular vesicles. a-Synuclein/HLA class II complexes were found in A2058 melanoma cells, which express intrinsic a-synuclein and HLA-DR with DRB5*01:01. Our findings will expand our knowledge of unconventional HLA class II function from autoimmune diseases to neurodegenerative disorders, shedding light on the association between the GWAS-prioritized PD-risk gene HLA-DR and a-synuclein. (c) 2023 Elsevier Inc. All rights reserved.