MicroRNA-7 Enhances Subventricular Zone Neurogenesis by Inhibiting NLRP3/Caspase-1 Axis in Adult Neural Stem Cells

alpha-Synuclein (alpha-syn) has been recognized to induce neuroinflammation and to disturb nerve repair process in Parkinson's disease. However, the potential mechanisms underlying alpha-syn-induced impairment of adult neurogenesis remain unclear. In the present study, A53T mutant alpha-Asynuclein transgenic (A53T(tg/tg)) mice, caspase-1 knockout mice, and A53T(tg/tg);caspase-1(-/-) double transgenic mice were used to prepare adult neural stem cells (ANSCs) and to investigate inflammasome-related mechanism for alpha-syn-impaired neurogenesis in mouse subventricular zone (SVZ). We showed that alpha-syn inhibited neurogenesis in the SVZ of A53T(tg/tg) mice and impaired proliferation and differentiation in ANSCs cultured in vitro, accompanied by reduced microRNA-7 (miR-7) expression levels. We further found that ANSC expressed NLRP3-containing inflammasome and alpha-syn activated both TLR4/NF-kappa B and NLRP3/caspase-1 signals in ANSCs. Either Nlrp3 knockdown or Caspase-1 knockout could attenuate the inhibition of proliferation in ANSCs induced by alpha-syn. Furthermore, we demonstrated that miR-7 post-transcriptionally controlled Nlrp3 expression besides targeting alpha-syn. Most notably, stereotactic injection of miR-7 mimics into lateral ventricles significantly inhibited NLRP3 inflammasome activation and improved adult neurogenesis in mouse SVZ. Our study provides a direct link between NLRP3 inflammasome activation and alpha-syn-impaired neurogenesis in the pathogenesis of alpha-synucleinopathies.