Microglia-derived exosomal ciRS-7 mediates IL-17A effect of promoting neurodegeneration via miR-7 and SNCA targets in an experimental Parkinson's disease

Parkinson' s disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra (SN). Our research has demonstrated that the levels of interleukin (IL)-17A are elevated in the SN of rodent models of PD, and that IL-17A accelerates neurodegeneration in PD depending on microglial activation. Furthermore, existing studies indicate that exosomes released by activated microglia may play a significant role as mediators of neurodegeneration in PD. Herein, we demonstrated that BV-2-derived exosomes were taken up by ventral mesencephalic (VM) dopaminergic neurons, and mediated IL-17A effect of promoting dopaminergic neuronal injury. IL-17A-treated BV-2-derived exosomes altered neuronal miR-7 and SNCA expression and promoted dopaminergic neuronal injury in vitro. Inhibiting BV-2 exosome formation and secretion by GW4869 alleviated dopaminergic neuronal injury. Silencing ciRS-7 in BV-2 altered neuronal miR-7 and SNCA expression and mitigated dopaminergic neuronal injury. Overexpression of ciRS-7 in VM neurons altered neuronal miR-7 and SNCA expression and promoted dopaminergic neuronal injury. Injection with exosomes derived from IL-17A-treated BV-2 altered ciRS-7, miR-7 and SNCA expression in SN in MPTP-intoxicated mice and promoted nigrostriatal dopaminergic neurodegeneration and motor impairment. However, injection with exosomes derived from IL-17A and ciRS-7-shRNA treated BV-2 attenuates the manifestations mentioned above. These findings suggest that microglia-derived exosomal ciRS-7 mediates IL-17A effect of promoting neurodegeneration via miR-7 and SNCA targets and may provide a new paradigm to study the pathology of PD.