OASI Institute for Research and Care on Mental Retardation and Brain Aging, Neuropharmacology Section, 94018 Troina, Italy.
J Neurosci. 2012 Feb 8;32(6):2062-85. doi: 10.1523/JNEUROSCI.5259-11.2012.
In Parkinson's disease (PD), neurogenesis is impaired in the subventricular zone (SVZ) of postmortem human PD brains, in primate nonhuman and rodent models of PD. The vital role of Wingless-type MMTV integration site (Wnt)/β-catenin signaling in the modulation of neurogenesis, neuroprotection, and synaptic plasticity coupled to our recent findings uncovering an active role for inflammation and Wnt/β-catenin signaling in MPTP-induced loss and repair of nigrostriatal dopaminergic (DAergic) neurons prompted us to study the impact of neuroinflammation and the Wnt/β-catenin pathway in the response of SVZ neuroprogenitors (NPCs) in MPTP-treated mice. In vivo experiments, using bromodeoxyuridine and cell-specific markers, and ex vivo time course analyses documented an inverse correlation between the reduced proliferation of NPCs and the generation of new neuroblasts with the phase of maximal exacerbation of microglia reaction, whereas a shift in the microglia proinflammatory phenotype correlated with a progressive NPC recovery. Ex vivo and in vitro experiments using microglia-NPC coculture paradigms pointed to NADPH-oxidase (gpPHOX(91)), a major source of microglial ROS, and reactive nitrogen species as candidate inhibitors of NPC neurogenic potential via the activation of glycogen synthase 3 (pGSK-3β(Tyr216)), leading to loss of β-catenin, a chief downstream transcriptional effector. Accordingly, MPTP/MPP(+) (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) caused β-catenin downregulation and pGSK-3β(Tyr216) overexpression, whereas manipulation of Wnt/β-catenin signaling with RNA interference-mediated GSK-3β knockdown or GSK-3β antagonism reversed MPTP-induced neurogenic impairment ex vivo/in vitro or in vivo. Reciprocally, pharmacological modulation of inflammation prevented β-catenin downregulation and restored neurogenesis, suggesting the possibility to modulate this endogenous system with potential consequences for DAergic neuroprotection and self-repair.
在帕金森病（PD）中，尸检人脑 PD 中脑室下区（SVZ）的神经发生受损，在灵长类非人类和啮齿动物 PD 模型中也是如此。Wingless 型 MMTV 整合位点（Wnt）/β-连环蛋白信号在神经发生、神经保护和突触可塑性调节中的重要作用，以及我们最近发现炎症和 Wnt/β-连环蛋白信号在 MPTP 诱导的黑质纹状体多巴胺能（DAergic）神经元丢失和修复中的积极作用，促使我们研究神经炎症和 Wnt/β-连环蛋白通路对 MPTP 处理小鼠 SVZ 神经祖细胞（NPC）反应的影响。体内实验，使用溴脱氧尿苷和细胞特异性标志物，以及体外时程分析，记录 NPC 增殖减少与新神经母细胞生成之间呈负相关，与小胶质细胞反应的最大加剧阶段一致，而小胶质细胞前炎症表型的转变与 NPC 的逐渐恢复相关。使用小胶质细胞-NPC 共培养模型的体外和体内实验表明，NADPH 氧化酶（gpPHOX（91）），小胶质细胞 ROS 的主要来源，以及活性氮物种作为 NPC 神经发生潜能的候选抑制剂，通过激活糖原合酶 3（pGSK-3β（Tyr216）），导致β-连环蛋白丢失，β-连环蛋白是主要的下游转录效应物。因此，MPTP/MPP+（1-甲基-4-苯基-1,2,3,6-四氢吡啶）导致β-连环蛋白下调和 pGSK-3β（Tyr216）过表达，而用 RNA 干扰介导的 GSK-3β 敲低或 GSK-3β 拮抗作用操纵 Wnt/β-连环蛋白信号，可逆转体外/体内或体内的 MPTP 诱导的神经发生损伤。相反，炎症的药理学调节可防止β-连环蛋白下调并恢复神经发生，这表明可以用潜在的 DAergic 神经保护和自我修复的后果来调节这种内源性系统。
