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

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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.

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Acknowledgments

The work reported herein was supported by the grants from the National Natural Science Foundation of China (No. 81473196, No. 81573403, No. 81202514, and No. 81202512), the National Science & Technology Major Project (No. 2012ZX09304-001), the Natural Science Foundation of Jiangsu Province (BK20130039), and the key project of Natural Science Foundation of the Higher Education Institutions of Jiangsu Province (No. 15KJA310002).

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    Authors and Affiliations

    1. Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, People’s Republic of China

      Zheng Fan, Ming Lu, Chen Qiao, Yan Zhou, Jian-Hua Ding & Gang Hu

    2. Biomedical Functional Materials Collaborative Innovation Center, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, 210023, Jiangsu, People’s Republic of China

      Gang Hu

    3. Department of Pharmacology, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, 210023, Jiangsu, People’s Republic of China

      Gang Hu

    4. Department of Pharmacology, Capital Medical University, 10 Xitoutiao, Youanmen, Beijing, 100069, People’s Republic of China

      Zheng Fan

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    1. Zheng Fan
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    Correspondence to Gang Hu.

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    Zheng Fan and Ming Lu contributed equally to this work.

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    ESM 1

    Phenotypic identification of cultured adult neural stem cells (ANSCs). (A) α-syn immunostaining in ANSCs. (B) Nestin immunostaining in ANSCs. Scale bar: 100 μm. (PDF 110 kb)

    ESM 2

    Phenotypic identification of ANSCs isolated from caspase-1+/+ and caspase-1−/− mice. (A) The morphological photo of neurospheres isolated from SVZ of caspase-1+/+ and caspase-1−/− mice. Scale bar: 100 μm. (B & C) Statistical analysis the number and diameter of neurospheres in both genotypic ANSCs. Data are expressed as mean ± S.E.M. from four independent experiments. (PDF 109 kb)

    ESM 3

    Luciferase report data show that miR-7 failed to inhibit Tlr4 gene expression. Data are expressed as mean ± S.E.M. from four independent experiments. (PDF 97 kb)

    ESM 4

    The protocol illustration of stereotactic injection and representative photo of injected miR-7 mimics in SVZ and striatum. Scale bar: 200 μm. (PDF 100 kb)

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    Fan, Z., Lu, M., Qiao, C. et al. MicroRNA-7 Enhances Subventricular Zone Neurogenesis by Inhibiting NLRP3/Caspase-1 Axis in Adult Neural Stem Cells. Mol Neurobiol 53, 7057–7069 (2016). https://doi.org/10.1007/s12035-015-9620-5

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