{"title":"Neuronal exosomal miRNAs modulate mitochondrial functions and cell death in bystander neuronal cells under Parkinson’s disease stress conditions","authors":"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","doi":"10.1016/j.neuro.2024.02.005","DOIUrl":null,"url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"101 ","pages":"Pages 102-116"},"PeriodicalIF":3.4000,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurotoxicology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0161813X24000196","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
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.
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.