Secretion and Uptake of α-Synuclein Via Extracellular Vesicles in Cultured Cells.
Secretion and Uptake of α-Synuclein Via Extracellular Vesicles in Cultured Cells.
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DOI：
10.1007/s10571-018-0622-5
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发表时间：
2018-11
影响因子：
4
通讯作者：
Ingelsson M
中科院分区：
文献类型：
--
作者：
Gustafsson G;Lööv C;Persson E;Lázaro DF;Takeda S;Bergström J;Erlandsson A;Sehlin D;Balaj L;György B;Hallbeck M;Outeiro TF;Breakefield XO;Hyman BT;Ingelsson M
在帕金森病和其他路易体疾病中，病理学的传播已被认为是细胞外 α-突触核蛋白 (α-syn) 的传播。尽管致病机制尚不完全清楚，但已报道α-syn通过外泌体和其他细胞外囊泡（EV）在细胞间转移。在这里，我们研究了改变 α-syn 的分子特性是否会影响 α-syn 在人神经母细胞瘤细胞中的分布和分泌。不同的 α-syn 变体，包括 α-syn:hemi-Venus 和致病突变体，被过度表达，并且从条件培养基中分离出 EV。在分泌的 α-syn 中，0.1-2% 与囊泡相关。 EV α-syn 的主要部分附着在囊泡的外膜上，而较小的部分则在囊泡的管腔中发现。对于用 N 端半金星表达的 α-syn，与 EV 相关的相对水平高于 WT α-syn。此外，这种与 EV 相关的 α-syn:hemi-Venus 物种在受体细胞中的内化程度高于相应的自由漂浮形式。在致病突变体中，A53T α-syn 与 EV 的关联性增强。综上所述，我们的数据表明，可能丧失生理功能或改变聚集特性的 α-syn 物种可能会将细胞处理转向囊泡分泌。因此，我们的研究结果进一步支持了这样的原则，即 EV 可以介导有害 α-syn 物种的传播，从而促进 α-突触核蛋白病的病理学。本文的在线版本 (10.1007/s10571-018-0622-5) 包含补充材料，可供授权用户使用。
In Parkinson’s disease and other Lewy body disorders, the propagation of pathology has been accredited to the spreading of extracellular α-synuclein (α-syn). Although the pathogenic mechanisms are not fully understood, cell-to-cell transfer of α-syn via exosomes and other extracellular vesicles (EVs) has been reported. Here, we investigated whether altered molecular properties of α-syn can influence the distribution and secretion of α-syn in human neuroblastoma cells. Different α-syn variants, including α-syn:hemi-Venus and disease-causing mutants, were overexpressed and EVs were isolated from the conditioned medium. Of the secreted α-syn, 0.1–2% was associated with vesicles. The major part of EV α-syn was attached to the outer membrane of vesicles, whereas a smaller fraction was found in their lumen. For α-syn expressed with N-terminal hemi-Venus, the relative levels associated with EVs were higher than for WT α-syn. Moreover, such EV-associated α-syn:hemi-Venus species were internalized in recipient cells to a higher degree than the corresponding free-floating forms. Among the disease-causing mutants, A53T α-syn displayed an increased association with EVs. Taken together, our data suggest that α-syn species with presumably lost physiological functions or altered aggregation properties may shift the cellular processing towards vesicular secretion. Our findings thus lend further support to the tenet that EVs can mediate spreading of harmful α-syn species and thereby contribute to the pathology in α-synucleinopathies. The online version of this article (10.1007/s10571-018-0622-5) contains supplementary material, which is available to authorized users.
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影响因子：
16.2
作者：
Giasson, BI;Duda, JE;Lee, VMY
通讯作者：
Lee, VMY
影响因子：
15.1
作者：
Danzer KM;Kranich LR;Ruf WP;Cagsal-Getkin O;Winslow AR;Zhu L;Vanderburg CR;McLean PJ
通讯作者：
McLean PJ
影响因子：
7.1
作者：
Lázaro DF;Dias MC;Carija A;Navarro S;Madaleno CS;Tenreiro S;Ventura S;Outeiro TF
通讯作者：
Outeiro TF
影响因子：
4.3
作者：
Delenclos M;Trendafilova T;Mahesh D;Baine AM;Moussaud S;Yan IK;Patel T;McLean PJ
通讯作者：
McLean PJ
影响因子：
6.2
作者：
Reyes, Juan F.;Rey, Nolwen L.;Angot, Elodie
通讯作者：
Angot, Elodie