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/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 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: Zheng Fan, Ming Lu, Chen Qiao, Yan Zhou, Jian-Hua Ding, Gang Hu
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 53 Issue 10 Pg. 7057-7069 (12 2016) ISSN: 1559-1182 [Electronic] United States
• PMID: 26676570 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Inflammasomes
• MIRN7 microRNA, mouse
• MicroRNAs
• NLR Family, Pyrin Domain-Containing 3 Protein
• alpha-Synuclein
• Caspase 1

Topics

• Adult Stem Cells (metabolism)
• Animals
• Caspase 1 (metabolism)
• Cell Differentiation
• Cell Proliferation
• Down-Regulation (genetics)
• Inflammasomes (metabolism)
• Lateral Ventricles (metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• MicroRNAs (genetics, metabolism)
• Mutation (genetics)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Neural Stem Cells (metabolism)
• Neurogenesis
• alpha-Synuclein (metabolism)