Znf179 於神經保護功能之探討

The Investigation on Neuroprotective Functions of Znf179

蘇子傑(Tzu-Chieh Su)

指導教授 ： 張文昌

共同指導教授 ： 李宜釗(Yi-Chao Lee)

臺北醫學大學/醫學院/醫學科學研究所/博士(2019年)

摘要

Znf179 為一腦指蛋白，在其結構上具有一個能與鋅離子結合的 RING domain。已知 Znf179 主要表現在神經細胞(neuron)，然而 研究也指出 Znf179 在活化的星形膠質細胞(astrocyte)中會受到 CCAAT/enhancer binding protein delta (CEBPD)蛋白的調控而增加 其表現量，並具有抑制星形膠質細胞凋亡的作用。為了探討 Znf179 是否對神經細胞也具有相同的保護作用，我們建立了能過度表現 (over-expressed)Znf179 的 neuro 2A (N2a) 細胞株，實驗結果發 現無論是在未分化或已誘導進行神經分化的細胞中，過度表現 Znf179 的細胞株對於 H2O2 所造成細胞傷害都具有較高的耐受性。進 一步探討則發現 Znf179 透過調控細胞內抗氧化蛋白如 Nrf2, SOD2, Prx3, and catalase 的表現來減少因 H2O2 處理而產生的活性氧物質 (Reactive oxygen species:ROS)的含量以達到保護細胞的作用。 此外，我們也發現 Znf179 能降低因 H2O2 處理而活化的細胞凋亡訊 號。有趣的是，我們發現 Znf179 可能透過與 Sigma-1 receptor 的結 合而參與在去氫皮質酮(DHEA)的神經保護作用。最後我們利用 創傷腦損傷模式，同樣的發現在 Znf179 轉殖小鼠腦部細胞中因創傷腦而誘發的細胞凋亡的訊號較正常小鼠低。綜合上述，我們的研究 結果證實 Znf179 在細胞以及動物模式中都具有神經保護的功能。

關鍵字

Znf179 ； 過氧化氫 ； 活性氧類 ； 神經保護

並列摘要

Znf179 is originally identified as brain finger protein which contains a RING domain. Although Znf179 is highly expressed in the neurons, the expression of Znf179 was also observed to be significantly up-regulated in activated astrocytes by CCAAT/enhancer binding protein delta (CEBPD) and played an anti-apoptotic role in astrocytes. To investigate whether Znf179 may also exert a protective role on neurons, we generated a neuro 2a (N2a) cell line with stably expressing Znf179 and found this cell line was more resistant to hydrogen peroxide toxicity than control cells in both neuronal differentiated and undifferentiated conditions. Further characterization revealed that Znf179 exerts its defensive via suppressing the generation and increasing the elimination of hydrogen peroxide-induced ROS. We also observed several increased antioxidant protein expressions, including Nrf2, SOD2, Prx3, and catalase. In addition, activation of cell death signaling following hydrogen peroxide treatment was also attenuated in N2a-Znf179 cells. Interestingly, we demonstrated that Znf179 may involve in the neuroprotective effect of neurosteroid, Dehydroepiandrosterone (DHEA), by interacting with Sigma-1 receptor. Finally, by utilizing traumatic brain injury model, we observed the activation of death signaling was also inhibited in the Znf179 transgenic mice. Our results provided the evidence for the neuroprotective function of Znf179 in an in vitro cell model and also an in vivo animal model.

並列關鍵字

Znf179 ； Hydrogen peroxide ； Reactive oxygen species ； Neuroprotection

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