Microglial exosomes facilitate α-synuclein transmission in Parkinson’s disease

作者：Min Guo, Jian Wang, Yanxin Zhao, Yiwei Feng, Sida Han, Qiang Dong, Mei Cui, Kim Tieu · 发表于：Brain · 年份：2020 · DOI：10.1093/brain/awaa090 · 被引用次数：537 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Neuroinflammation and Neurodegeneration Mechanisms、Nerve injury and regeneration

Accumulation of neuronal α-synuclein is a prominent feature in Parkinson's disease. More recently, such abnormal protein aggregation has been reported to spread from cell to cell and exosomes are considered as important mediators. The focus of such research, however, has been primarily in neurons. Given the increasing recognition of the importance of non-cell autonomous-mediated neurotoxicity, it is critical to investigate the contribution of glia to α-synuclein aggregation and spread. Microglia are the primary phagocytes in the brain and have been well-documented as inducers of neuroinflammation. How and to what extent microglia and their exosomes impact α-synuclein pathology has not been well delineated. We report here that when treated with human α-synuclein preformed fibrils, exosomes containing α-synuclein released by microglia are fully capable of inducing protein aggregation in the recipient neurons. Additionally, when combined with microglial proinflammatory cytokines, these exosomes further increased protein aggregation in neurons. Inhibition of exosome synthesis in microglia reduced α-synuclein transmission. The in vivo significance of these exosomes was demonstrated by stereotaxic injection of exosomes isolated from α-synuclein preformed fibrils treated microglia into the mouse striatum. Phosphorylated α-synuclein was observed in multiple brain regions consistent with their neuronal connectivity. These animals also exhibited neurodegeneration in the nigrostriatal p...