MicroRNA-7 Enhances Subventricular Zone Neurogenesis by Inhibiting NLRP3/Caspase-1 Axis in Adult Neural Stem Cells
MicroRNA-7 Enhances Subventricular Zone Neurogenesis by Inhibiting NLRP3/Caspase-1 Axis in Adult Neural Stem Cells
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MicroRNA-7 通过抑制成体神经干细胞中的 NLRP3/Caspase-1 轴来增强室下区神经发生
DOI：
10.1007/s12035-015-9620-5
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发表时间：
2016-12-01
影响因子：
5.1
通讯作者：
Hu, Gang
中科院分区：
文献类型：
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作者：
Fan, Zheng;Lu, Ming;Hu, Gang
α-突触核蛋白（alpha-synuclein，alpha-syn）被认为是帕金森病的神经炎症和神经修复障碍的重要因子。然而，潜在的机制α-syn诱导的成年神经发生障碍仍然不清楚。本研究采用A53 T突变型α-Asynuclein转基因小鼠（A53 T（tg/tg））、caspase-1基因敲除小鼠和A53 T（tg/tg）;caspase-1（-/-）双转基因小鼠制备成体神经干细胞（ANSC），并探讨炎症小体相关的α-syn损伤小鼠室管膜下区（SVZ）神经发生的机制。我们发现，alpha-syn抑制A53 T（tg/tg）小鼠SVZ的神经发生，并损害体外培养的ANSC的增殖和分化，同时降低microRNA-7（miR-7）表达水平。我们进一步发现ANSC表达含NLRP 3的炎性体，并且alpha-syn激活ANSC中的TLR 4/NF-κ B和NLRP 3/caspase-1信号。Nlrp 3基因敲除或Caspase-1基因敲除均能减弱α-syn对ANSC增殖的抑制作用。此外，我们证明了miR-7除了靶向alpha-syn外，还在转录后控制Nlrp 3的表达。最值得注意的是，将miR-7模拟物立体定向注射到侧脑室中显著抑制了NLRP 3炎性小体活化并改善了小鼠SVZ中的成体神经发生。我们的研究提供了在α-突触核蛋白病的发病机制中NLRP 3炎性小体激活和α-突触蛋白受损的神经发生之间的直接联系。
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.