Rotenone induced acute miRNA alterations in extracellular vesicles produce mitochondrial dysfunction and cell death.

How extracellular vesicles (EVs) may contribute to mechanisms of primary intracellular pathogenesis in Parkinson's disease (PD) remains unknown. To critically advance our understanding of how EVs influence early-stage PD pathogenesis, we tested the hypothesis that rats acutely exposed to the PD neurotoxin rotenone would produce differential miRNAs in CSF/serum-derived EVs and that such modulation would be responsible for PD-relevant functional alterations in recipient neuronal cells. We discovered that acute rotenone treatment produced significant and specific serum miRNA alterations. Primary midbrain neurons treated with serum EVs from rotenone-exposed rats produced oxidative stress, mitochondrial toxicity, and cell loss in neuronal culture. These mechanisms were dependent on miR-30a-5p and miR-484. Thus, this study has elucidated that differential expression of miRNAs in circulating EVs from serum/CSF of rats is a potential early diagnostic marker for PD, and that the modulation of cellular functions and viability due to extracellular vesicles determines the pathological fate.