title: MicroRNA-7 Enhances Subventricular Zone Neurogenesis by Inhibiting NLRP3/Caspase-1 Axis in Adult Neural Stem Cells.
abstract: α-Synuclein (α-syn) has been recognized to induce neuroinflammation and to disturb nerve repair process in Parkinson's disease. However, the potential mechanisms underlying α-syn-induced impairment of adult neurogenesis remain unclear. In the present study, A53T mutant α--synuclein transgenic (A53Ttg/tg) mice, caspase-1 knockout mice, and A53Ttg/tg;caspase-1-/-double transgenic mice were used to prepare adult neural stem cells (ANSCs) and to investigate inflammasome-related mechanism for α-syn-impaired neurogenesis in mouse subventricular zone (SVZ). We showed that α-syn inhibited neurogenesis in the SVZ of A53Ttg/tgmice 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 α-syn activated both TLR4/NF-κB and NLRP3/caspase-1 signals in ANSCs. Either Nlrp3 knockdown or Caspase-1 knockout could attenuate the inhibition of proliferation in ANSCs induced by α-syn. Furthermore, we demonstrated that miR-7 post-transcriptionally controlled Nlrp3 expression besides targeting α-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 α-syn-impaired neurogenesis in the pathogenesis of α-synucleinopathies.
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, People's Republic of China.|Department of Pharmacology, Capital Medical University, 10 Xitoutiao, Youanmen, Beijing, 100069, People's Republic of China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lu
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, People's Republic of China.
authors.forename: Chen
authors.initials: C
authors.lastname: Qiao
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, People's Republic of China.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Ding
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, People's Republic of China. ghu@njmu.edu.cn.|Biomedical Functional Materials Collaborative Innovation Center, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, 210023, Jiangsu, People's Republic of China. ghu@njmu.edu.cn.|Department of Pharmacology, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, 210023, Jiangsu, People's Republic of China. ghu@njmu.edu.cn.
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism*; D000818:Animals; D020170:Caspase 1 / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics; D058847:Inflammasomes / Q000378:metabolism; D020547:Lateral Ventricles / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism*; D055495:Neurogenesis; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D058847:Inflammasomes; C549243:MIRN7 microRNA, mouse; D035683:MicroRNAs; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D051844:alpha-Synuclein; D020170:Caspase 1
keywords: NLRP3 inflammasome; Neural stem cell; Neurogenesis; Parkinson’s disease; microRNA-7