Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, Gujarat, India.
Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi UP 221005, India.
Int J Biochem Cell Biol. 2023 Sep;162:106439. doi: 10.1016/j.biocel.2023.106439. Epub 2023 Jul 8.
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal cell death. Emerging evidence suggest exosomes as a crucial player in the progression and pathogenesis of PD via intercellular communication between different cell types in brain. Exosome release is enhanced from dysfunctional neurons/glia (source cells) under PD stress and mediates the transfer of biomolecules between different cell types (recipient) in brain leading to unique functional outcomes. Exosome release is modulated by alterations in the autophagy and lysosomal pathways; however, the molecular factors regulating these pathways remain elusive. Micro-RNAs (miRNAs) are class of non-coding RNAs that regulate gene expression post-transcriptionally by binding target mRNA and modulate its turnover and translation; however their role in modulating exosome release is not understood. Here, we analyzed the miRNAs-mRNAs network which target cellular processes regulating exosome release. hsa-miR-320a showed the maximum mRNA targets of autophagy, lysosome, mitochondria and exosome release pathways. hsa-miR-320a regulate ATG5 levels and modulate exosome release under PD stress conditions in neuronal SH-SY5Y and glial U-87 MG cells. hsa-miR-320a modulates autophagic flux, lysosomal functions, and mitochondrial ROS in neuronal SH-SY5Y and glial U-87 MG cells. Exosomes derived from hsa-miR-320a expressing source cells under PD stress conditions were actively internalized in the recipient cells and rescued cell death and mitochondrial ROS. These results suggest that hsa-miR-320a regulates autophagy and lysosomal pathways and modulates exosome release in the source cells and derived exosomes under PD stress conditions rescue cell death and mitochondrial ROS in the recipient neuronal and glial cells.
帕金森病（PD）是一种进行性神经退行性疾病，其特征是多巴胺能神经元细胞死亡。新出现的证据表明，外泌体通过脑内不同细胞类型之间的细胞间通讯，在 PD 的进展和发病机制中起着至关重要的作用。在 PD 应激下，功能失调的神经元/神经胶质（源细胞）中外泌体的释放增强，并介导脑内不同细胞类型（受体）之间生物分子的转移，从而导致独特的功能结果。外泌体的释放受自噬和溶酶体途径改变的调节；然而，调节这些途径的分子因素仍然难以捉摸。微小 RNA（miRNA）是一类非编码 RNA，通过与靶 mRNA 结合并调节其周转率和翻译来在后转录水平上调节基因表达；然而，它们在调节外泌体释放中的作用尚不清楚。在这里，我们分析了针对调节外泌体释放的细胞过程的 miRNA-mRNA 网络。hsa-miR-320a 显示了自噬、溶酶体、线粒体和外泌体释放途径的最大 mRNA 靶标。hsa-miR-320a 在神经元 SH-SY5Y 和神经胶质 U-87 MG 细胞中调节 PD 应激条件下的 ATG5 水平并调节外泌体释放。hsa-miR-320a 调节神经元 SH-SY5Y 和神经胶质 U-87 MG 细胞中的自噬流、溶酶体功能和线粒体 ROS。源自 PD 应激条件下表达 hsa-miR-320a 的源细胞的外泌体在受体细胞中被主动内化，并挽救细胞死亡和线粒体 ROS。这些结果表明，hsa-miR-320a 调节自噬和溶酶体途径，并调节 PD 应激条件下源细胞和衍生外泌体中的外泌体释放，挽救受体神经元和神经胶质细胞中的细胞死亡和线粒体 ROS。
