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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival.
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Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival.

机译：细胞产生的α-突触核蛋白通过外泌体以钙依赖性方式分泌，并影响神经元存活。

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摘要

alpha-Synuclein is central in Parkinson's disease pathogenesis. Although initially alpha-synuclein was considered a purely intracellular protein, recent data suggest that it can be detected in the plasma and CSF of humans and in the culture media of neuronal cells. To address a role of secreted alpha-synuclein in neuronal homeostasis, we have generated wild-type alpha-synuclein and beta-galactosidase inducible SH-SY5Y cells. Soluble oligomeric and monomeric species of alpha-synuclein are readily detected in the conditioned media (CM) of these cells at concentrations similar to those observed in human CSF. We have found that, in this model, alpha-synuclein is secreted by externalized vesicles in a calcium-dependent manner. Electron microscopy and liquid chromatography-mass spectrometry proteomic analysis demonstrate that these vesicles have the characteristic hallmarks of exosomes, secreted intraluminar vesicles of multivesicular bodies. Application of CM containing secreted alpha-synuclein causes cell death of recipient neuronal cells, which can be reversed after alpha-synuclein immunodepletion from the CM. High- and low-molecular-weight alpha-synuclein species, isolated from this CM, significantly decrease cell viability. Importantly, treatment of the CM with oligomer-interfering compounds before application rescues the recipient neuronal cells from the observed toxicity. Our results show for the first time that cell-produced alpha-synuclein is secreted via an exosomal, calcium-dependent mechanism and suggest that alpha-synuclein secretion serves to amplify and propagate Parkinson's disease-related pathology.
机译：α-突触核蛋白是帕金森病发病机制中的中心。虽然初始α-突触核蛋白被认为是纯粹的细胞内蛋白，但最近的数据表明它可以在人类和神经元细胞的培养基中检测到它的血浆和CSF。为了解决分泌的α-突触核蛋白在神经元稳态中的作用，我们产生了野生型α-突触核蛋白和β-半乳糖苷酶诱导的SH-SY5Y细胞。可溶性低聚和单体物种在这些细胞的条件培养基（CM）中以与在人CSF中观察到的浓度的浓度中被容易地检测到α-突触核蛋白。我们发现，在该模型中，α-突触核蛋白通过钙依赖性方式被外化囊泡分泌。电子显微镜和液相色谱 - 质谱蛋白质组学分析表明，这些囊泡具有外泌体的特征标志，分泌的多猪体内的胰蛋白酶囊泡。含有分泌的α-突触核蛋白的CM的施用导致受体神经元细胞的细胞死亡，其在来自CM的α-突触核蛋白免疫普除中可以逆转。从该厘米分离的高分子和低分子量的α-突触核蛋白物质，显着降低细胞活力。重要的是，在施用之前，用低聚物干扰化合物处理CM与观察到的毒性救出受体神经元细胞。我们的结果首次显示细胞产生的α-突触核蛋蛋白通过外泌体，钙依赖性机制分泌，并表明α-突触核蛋白分泌用于扩增和繁殖帕金森病相关病理学。

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