Neuronal exosomal miRNAs modulate mitochondrial functions and cell death in bystander neuronal cells under Parkinson’s disease stress conditions

IF 3.4 3区 医学 Q2 NEUROSCIENCES Neurotoxicology Pub Date : 2024-03-01 DOI:10.1016/j.neuro.2024.02.005
Fatema Currim , Shatakshi Shukla , Jyoti Singh , Dhruv Gohel , Minal Mane , Anjali Shinde , Milton Roy , Shani Goyani , Hitesh Vasiyani , Aswathy Chandran , Jean-Christophe Rochet , Jason Cannon , Rajesh Singh
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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.

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神经元外泌体 miRNA 在帕金森病应激条件下调节旁观者神经元细胞的线粒体功能和细胞死亡。
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的中脑多巴胺能神经元逐渐丧失。病理变化遍及多个脑区和细胞类型,这表明细胞间的交流对帕金森病的进展至关重要。外泌体介导了整个帕金森病相关脑区的神经元、胶质细胞和其他细胞类型之间的细胞间通信。然而,其机制仍不清楚,对其在帕金森病病理中的影响也不甚了解。在本研究中,我们探讨了外泌体在调节对帕金森病相关毒性物质的反应中的作用。在帕金森病的细胞模型中,神经元细胞衍生的外泌体很容易作为完整的囊泡被受体神经元细胞内化。旁观者神经元细胞中内化的外泌体定位到线粒体,并使线粒体功能失调,导致细胞在帕金森病应激条件下死亡。对受到帕金森病应激条件影响的神经元细胞释放的外泌体进行的NGS分析表明,在帕金森病应激条件下,外泌体中特定miRNA的水平发生了改变。对miRNA靶标的生物信息学分析表明,与神经元过程和形态发生、细胞凋亡和衰老有关的通路得到了丰富。在帕金森病应激条件下,外泌体中两种 miRNA(hsa-miR-30a-5p 和 hsa-miR-181c-5p)的水平下调。在神经元细胞中表达已确定的 miRNA 可使它们在外泌体中富集,神经元细胞对外泌体的摄取可改善帕金森病应激条件下诱发的线粒体功能障碍并挽救细胞死亡。总之,在帕金森病应激条件下,特定miRNA(包括miR-30a-5p和miR-181c-5p)富集的丧失会导致线粒体功能障碍和神经元死亡,从而可能导致帕金森病的进展。
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来源期刊
Neurotoxicology
Neurotoxicology 医学-毒理学
CiteScore
6.80
自引率
5.90%
发文量
161
审稿时长
70 days
期刊介绍: NeuroToxicology specializes in publishing the best peer-reviewed original research papers dealing with the effects of toxic substances on the nervous system of humans and experimental animals of all ages. The Journal emphasizes papers dealing with the neurotoxic effects of environmentally significant chemical hazards, manufactured drugs and naturally occurring compounds.
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