Extracellular transportation of α-synuclein by HLA class II molecules
Extracellular transportation of α-synuclein by HLA class II molecules
复制标题
HLA II 类分子对 α-突触核蛋白的细胞外运输
DOI：
10.1016/j.bbrc.2022.12.082
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发表时间：
2023
影响因子：
3.1
通讯作者：
et al
中科院分区：
文献类型：
--
作者：
Tatsuhiko Ozono;et al
帕金森病（PD）是一种神经退行性疾病，其特征是α-突触核蛋白聚集体以路易小体的形式进行性积累。全基因组关联研究表明，人类白细胞抗原（HLA） II类是PD相关基因，尽管HLA II类与PD之间的联系机制尚不明确。在这里，我们发现HLA II类在细胞内α-突触核蛋白转运到细胞外的新功能。HLA II类分子与α-突触核蛋白在HLA- dr等位基因之间形成复合物，并不同程度地向细胞表面移动。HLA-DR具有DRB5 * 01:01等位基因，这是一种假定的pd风险等位基因，将正常和构象异常的α-突触核蛋白大量易位到细胞表面和细胞外囊泡。α-Synuclein/HLA II类复合物在A2058黑色素瘤细胞中被发现，其表达内在α-Synuclein和HLA- dr， DRB5∗01:01。我们的发现将扩大我们对从自身免疫性疾病到神经退行性疾病的非常规HLA II类功能的认识，揭示gwas优先的pd风险基因HLA- dr和α-突触核蛋白之间的关系。
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of α-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 α-synuclein to the outside of cells. HLA class II molecules and α-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 α-synuclein to the cell surface and extracellular vesicles. α-Synuclein/HLA class II complexes were found in A2058 melanoma cells, which express intrinsic α-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 α-synuclein.