Abstract：
Parkinson\'s Disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of midbrain dopaminergic neurons in the substantia nigra part of the brain. Pathology spread to numerous brain regions and cell types suggests that intercellular communication is essential to PD progression. Exosomes mediate intercellular communication between neurons, glia, and other cell types throughout PD-relevant brain regions. However, the mechanism remains unclear, and its implication in PD pathology, is not well understood. In the current study, we explored the role of exosomes in modulating the response to PD-relevant toxicants. In cellular models of PD, neuronal cell-derived exosomes are readily internalized by recipient neuronal cells as intact vesicles. Internalized exosomes in bystander neuronal cells localize to mitochondria and dysregulate mitochondrial functions, leading to cell death under PD stress conditions. NGS analysis of exosomes released by neuronal cells subjected to PD stress conditions showed that levels of specific miRNAs were altered in exosomes under PD stress conditions. Bioinformatic analysis of the miRNA targets revealed enriched pathways related to neuronal processes and morphogenesis, apoptosis and ageing. Levels of two miRNAs, hsa-miR-30a-5p and hsa-miR-181c-5p, were downregulated in exosomes under PD stress conditions. Expression of the identified miRNAs in neuronal cells led to their enrichment in exosomes, and exosome uptake in neuronal cells ameliorated mitochondrial dysfunction induced by PD stress conditions and rescued cell death. In conclusion, loss of enrichment of specific miRNAs, including miR-30a-5p and miR-181c-5p, under PD stress conditions causes mitochondrial dysfunction and neuronal death, and hence may lead to progression of PD.
摘要：
帕金森病（PD）是一种慢性神经退行性疾病，其特征是大脑黑质部分中脑多巴胺能神经元的进行性丧失。病理学传播到许多脑区和细胞类型表明，细胞间通讯对PD进展至关重要。外泌体介导神经元之间的细胞间通讯，glia,以及整个PD相关大脑区域的其他细胞类型。然而,机制尚不清楚,以及它在PD病理学中的意义，不是很了解。在目前的研究中,我们探讨了外泌体在调节PD相关毒物应答中的作用.在PD的细胞模型中，神经元细胞来源的外泌体很容易被受体神经元细胞内化为完整的囊泡。旁观者神经元细胞内化的外泌体定位于线粒体，线粒体功能失调，导致PD应激条件下的细胞死亡。由经受PD应激条件的神经元细胞释放的外来体的NGS分析显示,在PD应激条件下,外来体中特定miRNA的水平改变。miRNA靶标的生物信息学分析揭示了与神经元过程和形态发生相关的富集途径，凋亡，和衰老。两种miRNA的水平,hsa-miR-30a-5p和hsa-miR-181c-5p，在PD胁迫条件下，外泌体下调。鉴定的miRNA在神经元细胞中的表达导致它们在外泌体中的富集,神经元细胞外泌体的摄取改善了PD应激条件诱导的线粒体功能障碍并挽救了细胞死亡。总之,特定miRNA的富集丢失，包括miR-30a-5p和miR-181c-5p，在PD应激条件下导致线粒体功能障碍和神经元死亡，因此可能导致PD的进展。
