Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China.
Department of Pathology, University of Washington School of Medicine, 325 9th Ave, HMC Box 359635, Seattle, WA 98104, USA.
Brain. 2020 Jun 1;143(6):1780-1797. doi: 10.1093/brain/awaa110.
Transportation of key proteins via extracellular vesicles has been recently implicated in various neurodegenerative disorders, including Parkinson's disease, as a new mechanism of disease spreading and a new source of biomarkers. Extracellular vesicles likely to be derived from the brain can be isolated from peripheral blood and have been reported to contain higher levels of α-synuclein (α-syn) in Parkinson's disease patients. However, very little is known about extracellular vesicles in multiple system atrophy, a disease that, like Parkinson's disease, involves pathological α-syn aggregation, though the process is centred around oligodendrocytes in multiple system atrophy. In this study, a novel immunocapture technology was developed to isolate blood CNPase-positive, oligodendrocyte-derived enriched microvesicles (OEMVs), followed by fluorescent nanoparticle tracking analysis and assessment of α-syn levels contained within the OEMVs. The results demonstrated that the concentrations of OEMVs were significantly lower in multiple system atrophy patients, compared to Parkinson's disease patients and healthy control subjects. It is also noted that the population of OEMVs involved was mainly in the size range closer to that of exosomes, and that the average α-syn concentrations (per vesicle) contained in these OEMVs were not significantly different among the three groups. The phenomenon of reduced OEMVs was again observed in a transgenic mouse model of multiple system atrophy and in primary oligodendrocyte cultures, and the mechanism involved was likely related, at least in part, to an α-syn-mediated interference in the interaction between syntaxin 4 and VAMP2, leading to the dysfunction of the SNARE complex. These results suggest that reduced OEMVs could be an important mechanism related to pathological α-syn aggregation in oligodendrocytes, and the OEMVs found in peripheral blood could be further explored for their potential as multiple system atrophy biomarkers.
细胞外囊泡（extracellular vesicles）转运关键蛋白已被新近发现与多种神经退行性疾病有关，包括帕金森病，这是一种疾病传播的新机制和生物标志物的新来源。源自大脑的细胞外囊泡很可能可以从外周血中分离出来，并且已经有报道称帕金森病患者的细胞外囊泡中含有更高水平的α-突触核蛋白（α-syn）。然而，对于多系统萎缩症（multiple system atrophy，MSA）中的细胞外囊泡，我们知之甚少。多系统萎缩症与帕金森病一样，涉及病理性α-突触核蛋白聚集，但该过程主要集中在多系统萎缩症的少突胶质细胞中。在这项研究中，开发了一种新的免疫捕获技术来分离血液 CNPase 阳性、少突胶质细胞衍生的富含微泡（oligodendrocyte-derived enriched microvesicles，OEMVs），然后进行荧光纳米颗粒跟踪分析并评估 OEMVs 中包含的α-syn 水平。结果表明，与帕金森病患者和健康对照组相比，多系统萎缩症患者的 OEMVs 浓度显著降低。还注意到，OEMVs 的群体主要集中在更接近外泌体大小范围的范围内，并且这三组 OEMVs 中所含的平均α-syn 浓度（每个囊泡）没有显著差异。在多系统萎缩症的转基因小鼠模型和原代少突胶质细胞培养物中再次观察到 OEMVs 减少的现象，涉及的机制可能至少部分与α-syn 介导的 syntaxin 4 和 VAMP2 之间相互作用的干扰有关，导致 SNARE 复合物的功能障碍。这些结果表明，OEMVs 的减少可能是与少突胶质细胞中病理性α-突触核蛋白聚集相关的重要机制，并且在外周血中发现的 OEMVs 可能因其作为多系统萎缩症生物标志物的潜力而进一步得到探索。
