Exosomal cell-to-cell transmission of alpha synuclein oligomers.
Exosomal cell-to-cell transmission of alpha synuclein oligomers.
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DOI：
10.1186/1750-1326-7-42
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发表时间：
2012-08-24
影响因子：
15.1
通讯作者：
McLean PJ
中科院分区：
文献类型：
--
作者：
Danzer KM;Kranich LR;Ruf WP;Cagsal-Getkin O;Winslow AR;Zhu L;Vanderburg CR;McLean PJ
α-突触核蛋白（αsyn）的聚集和产生的细胞毒性是散发性和家族性帕金森病（PD）以及路易体痴呆的标志，最近的证据表明αsyn的寡聚体和前纤维形式是致病物质。最近的体外研究支持细胞外分泌的αsyn跨膜跨细胞传播的想法。本研究的目的是表征αsyn寡聚体的跨细胞扩散并确定其细胞外定位。使用一种新的蛋白质片段互补试验，其中αsyn与人源化Gaussia荧光素酶的非生物发光氨基或羧基末端片段融合，我们在这里证明αsyn寡聚体可以在至少两种细胞外组分中发现：与外泌体相关或游离。与游离α-syn寡聚体相比，外来体相关的α-syn寡聚体更可能被受体细胞摄取，并且可以诱导更多的毒性。具体来说，我们确定αsyn寡聚体存在于外泌体的外部和内部。值得注意的是，αsyn寡聚体的分泌途径受到自噬活性的强烈影响。我们的数据表明，αsyn可能通过不同的分泌途径分泌。我们假设外泌体介导的α-syn寡聚体的释放是一种机制，当自噬机制不充分时，细胞可以清除有毒的α-syn寡聚体。通过诱导自噬来预防αsyn外泌体释放和摄取的早期事件可能是阻止PD和其他突触核蛋白病中疾病传播的新方法。
Aggregation of alpha-synuclein (αsyn) and resulting cytotoxicity is a hallmark of sporadic and familial Parkinson’s disease (PD) as well as dementia with Lewy bodies, with recent evidence implicating oligomeric and pre-fibrillar forms of αsyn as the pathogenic species. Recent in vitro studies support the idea of transcellular spread of extracellular, secreted αsyn across membranes. The aim of this study is to characterize the transcellular spread of αsyn oligomers and determine their extracellular location. Using a novel protein fragment complementation assay where αsyn is fused to non-bioluminescent amino-or carboxy-terminus fragments of humanized Gaussia Luciferase we demonstrate here that αsyn oligomers can be found in at least two extracellular fractions: either associated with exosomes or free. Exosome-associated αsyn oligomers are more likely to be taken up by recipient cells and can induce more toxicity compared to free αsyn oligomers. Specifically, we determine that αsyn oligomers are present on both the outside as well as inside of exosomes. Notably, the pathway of secretion of αsyn oligomers is strongly influenced by autophagic activity. Our data suggest that αsyn may be secreted via different secretory pathways. We hypothesize that exosome-mediated release of αsyn oligomers is a mechanism whereby cells clear toxic αsyn oligomers when autophagic mechanisms fail to be sufficient. Preventing the early events in αsyn exosomal release and uptake by inducing autophagy may be a novel approach to halt disease spreading in PD and other synucleinopathies.
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