Environmental neurotoxicant manganese regulates exosome-mediated extracellular miRNAs in cell culture model of Parkinson's disease: Relevance to α-synuclein misfolding in metal neurotoxicity.
Environmental neurotoxicant manganese regulates exosome-mediated extracellular miRNAs in cell culture model of Parkinson's disease: Relevance to α-synuclein misfolding in metal neurotoxicity.
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DOI：
10.1016/j.neuro.2017.04.007
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发表时间：
2018-01
期刊：
影响因子：
3.4
通讯作者：
Kanthasamy AG
中科院分区：
文献类型：
--
作者：
Harischandra DS;Ghaisas S;Rokad D;Zamanian M;Jin H;Anantharam V;Kimber M;Kanthasamy A;Kanthasamy AG
许多慢性神经退行性疾病都有共同的致病机制，包括错误折叠的蛋白质聚集和沉积。最近，有研究表明，这些聚集的蛋白质可以通过称为外体的细胞外纳米囊泡从一个细胞转移到另一个细胞。外切体最初被认为是一种清除细胞废物的手段，后来被发现积极参与细胞间的通讯。重要的是，各种炎症和信号分子以及小RNA被选择性地包装在这些小泡中。考虑到环境中的锰在帕金森病(PD)样神经疾病中的重要作用，我们利用稳定表达野生型人α-突触核蛋白(αSyn)的PD的MN9D多巴胺能细胞模型来表征Mn对外切体含量和释放的影响。纳米颗粒分析和电子显微镜观察表明，30 0μMMnCl2作用2 4h后，细胞外的外切体先释放到胞外介质中，而后发生细胞毒性。值得注意的是，Western印迹分析表明，在表达αSYN的细胞中，锰处理增加了调节细胞外切体释放的蛋白Rab27a。此外，下一代测序显示，从暴露于锰的细胞中分离的外体中的小RNA比对照外体中的更多。我们的miRNA图谱分析导致发现某些先前被证明调节关键生物途径的miRNAs表达增加，包括蛋白质聚集、自噬、炎症和缺氧。总而言之，我们的结果提供了一个关于MN通过多巴胺能神经元细胞胞外释放调节细胞外miRNA含量的作用，从而潜在地促进了进行性神经退变。对细胞外miRNAs及其靶点的进一步表征将对包括帕金森病在内的环境相关神经退行性疾病的生物标记物的发现和翻译策略产生重大影响。
Many chronic neurodegenerative disorders share a common pathogenic mechanism involving the aggregation and deposition of misfolded proteins. Recently, it was shown that these aggregated proteins could be transferred from one cell to another via extracellular nanovesicles called exosomes. Initially thought to be a means of cellular waste removal, exosomes have since been discovered to actively participate in cell-to-cell communication. Importantly, various inflammatory and signaling molecules, as well as small RNAs are selectively packaged in these vesicles. Considering the important role of environmental manganese (Mn) in Parkinson’s disease (PD)-like neurological disorders, we characterized the effect of Mn on exosome content and release using an MN9D dopaminergic cell model of PD, which was generated to stably express wild-type human α-synuclein (αSyn). Mn exposure (300 μM MnCl2) for 24 h induced the release of exosomes into the extracellular media prior to cytotoxicity, as determined by NanoSight particle analysis and electron microscopy. Strikingly, Western blot analysis revealed that Mn treatment in αSyn-expressing cells increases the protein Rab27a, which regulates the release of exosomes from cells. Moreover, next-generation sequencing showed more small RNAs in exosomes isolated from Mn-exposed cells than the control exosomes. Our miRNA profiling analysis led to the discovery of increased expression of certain miRNAs previously shown to regulate key biological pathways, including protein aggregation, autophagy, inflammation and hypoxia. Collectively, our results provide a glimpse of Mn’s role in modulating extracellular miRNA content through exosomal release from dopaminergic neuronal cells and thus potentially contributing to progressive neurodegeneration. Further characterization of extracellular miRNAs and their targets will have major impacts on biomarker discovery and translational strategies for environmentally linked neurodegenerative diseases including PD.
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影响因子：
--
作者：
Chen, Christopher Y.;Hogan, Marie C.;Ward, Christopher J.
通讯作者：
Ward, Christopher J.
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：
12.4
作者：
Bo, L.;Su-Ling, D.;Pei-Feng, L.
通讯作者：
Pei-Feng, L.
DOI：
10.1196/annals.1306.009
发表时间：
2004-01-01
期刊：
REDOX-ACTIVE METALS IN NEUROLOGICAL DISORDERS
影响因子：
--
作者：
Dobson, AW;Erikson, KM;Aschner, M
通讯作者：
Aschner, M
影响因子：
4.8
作者：
Doxakis, Epaminondas
通讯作者：
Doxakis, Epaminondas