hsa-miR-22-3p-Mediated Exosome Release From Neurons Induces Apoptosis in Recipient Glial and Neuronal Cells in Parkinson's Disease Stress Conditions

Exosome-mediated intercellular communication between different cell types and brain regions is essential for the homeostasis of the nervous system and any dysfunctions lead to the progression of several neurodegenerative disorders including Parkinson's disease (PD). Exosome biogenesis and release from the specific cell types are modulated by interorganellar crosstalk, and the transfer of exosomal cargo influences the functional outcome in the recipient cells. The miRNA–mRNA interaction modulates mRNA translation and stability; yet the understanding of specific miRNAs modulating exosome release in neuronal cells during PD stress is not well characterized. Bioinformatics analysis of different databases identified the putative mRNA targets for hsa-miR-22-3p suggesting its regulatory role in pathways of exosome release, autophagy and apoptosis. hsa-miR-22-3p levels were downregulated in neuronal SH-SY5Y cells under PD stress conditions induced by 6-OHDA and rotenone. hsa-miR-22-3p expression downregulates LAMP1, BCL2 and p62 protein levels in neuronal cells, impairing autophagic flux and mitochondrial-lysosomal functions, enhancing exosome release. Exosomes derived from hsa-miR-22-3p-expressing neuronal cells were actively internalized by glial and neuronal cells, exhibiting distinctive morphological features and cell death. The present study highlights the role of hsa-miR-22-3p in modulating the interorganelle communication, influencing exosome release and exacerbating neuronal and glial cell death during PD stress conditions.