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研究生：	謝嘉芸 Hsieh, Chia-Yun
論文名稱：	探討冷誘導核醣核酸結合蛋白在低溫對抗MPP+毒性的神經保護作用中所扮演之角色 The role of cold-inducible RNA binding protein in the neuroprotection of hypothermia against MPP+ toxicity
指導教授：	莊季瑛 Chuang, Jih-Ing
學位類別：	碩士 Master
系所名稱：	醫學院 - 生理學研究所 Department of Physiology
論文出版年：	2015
畢業學年度：	103
語文別：	英文
論文頁數：	60
中文關鍵詞：	低溫、CIRBP 、Nrf2 、MPP+ 、神經保護
外文關鍵詞：	hypothermia, CIRBP, Nrf2, MPP+, neuroprotection
相關次數：	點閱：132 下載：0
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低溫治療目前已經被認為是一個具有潛力去阻止廣泛腦損傷的治療方式。我們之前的研究以人類神經母細胞瘤細胞株 (SK-N-SH cell line) 在低溫 (32C) 處理後發現，細胞株會大量的表達冷所誘導的核糖核酸結合蛋白(cold-inducible RNA binding protein, CIRBP)，這個大量表達的蛋白在低溫下所扮演的功能，目前為止還不是很清楚。因此，我們想要探討冷誘導核糖核酸結合蛋白在低溫對抗MPP+毒性的神經保護作用當中所扮演的角色。MPP+是一個粒線體中呼吸鏈上複合體I (complex I) 的抑制劑，此藥物可以廣泛且選擇性的造成多巴胺神經的死亡，因此是一種常被用來模擬帕金森氏症的藥物。首先，我們發現SK-N-SH 細胞株暴露在低溫下24 h 可以顯著的降低內源性及MPP+所誘導H2O2產生，接著，低溫可以顯著降低細胞死亡率以及增加細胞的存活率。文獻已指出，轉錄因子-Nrf2，可以被氧化壓力活化，並促進下游抗氧化酵素的轉錄，包含-穀氨醯半胱氨酸合成酶 (-GCS)、第一型血紅素氧化酶 (HO-1) 及NAD(P)H對苯二酮脫氫酶 (NQO1)，進而去抑制氧化壓力，達到細胞保護的作用。我們探討Nrf2抗氧化系統是否涉及低溫誘導保護作用機制，在低溫暴露下，依序會提高下列mRNA分子或蛋白的表現：1 h下，細胞核中Nrf2蛋白及HO-1 mRNA表現； 6 h, -GCSc 蛋白及 HO-1 mRNA表現; 12 h, HO-1 mRNA表現; 12 h-48 h, RBM3 mRNA表現; 24 h會提高 -GCSc蛋白表現; 24-48 h會提高CIRBP mRNA表現。低溫處理也抑制MPP+所誘導CIRBP、 -GCSc及RBM3 (another cold-inducible protein) mRNA下降以及HO-1及NQO-1 mRNA上升。低溫還可以避免MPP+誘導ARE啟動子活性下降。接著，我們分別將pEGFP-N1融合蛋白及pLKO.AS3w.puro vectors 插入一段人類全長cirbp 基因去大量表達CIRBP。我們發現轉染cirbp-EGFP 融合蛋白質體或共同轉染 cirbp/puromycin plasmid 以及 ARE-pGL3 plasmid，顯著降低MPP+誘導細胞死亡，然而單獨轉染cirbp/puromycin plasmid卻沒有保護作用，並且會誘發H2O2含量增高。另外，大量表達CIRBP在MPP+誘導Nrf2所調控抗氧化酵素的改變以及對神經細胞的保護作用中，並沒有像低溫處理一樣明顯。我們繼續探討這樣不同的結果是否是因為CIRBP表達在細胞中不同位置所造成的影響。利用免疫螢光染色及表達cirbp-EGFP 融合蛋白的實驗中，我們發現不管細胞處於低溫或大量表達CIRBP或MPP+處理之下，都可以看到細胞核的CIRBP表現量高於細胞質。這樣的結果暗示，CIRBP在低溫誘導的神經保護作用機制當中，只扮演了部分的角色。

Hypothermia has a promising therapeutic advantage in the prevention of a broad range of brain damages. Our preliminary results showed that human SK-N-SH neuroblastoma cells cultured in cold condition (32C) significantly upregulated the cold-inducible RNA binding protein (CIRBP) expression. However, the function of CIRBP upregulation under cold exposure is unclear. Herein, we investigated the role of CIRBP in cold exposure-induced neuroprotection against 1-methyl-4-phenylpyridinium (MPP+) toxicity. MPP+ is an inhibitor of mitochondrial complex I and widely used to selectively induced dopaminergic neuron death as a model of Parkinson’s disease. Firstly, we found that cold exposure for 24 h significantly reduced endogenous and MPP+-induced H2O2 production, and subsequently prevented neuron death 48 h after MPP+ treatment. Because it has been reported that transcription factor of nuclear factor erythroid 2-related factor 2 (Nrf2) is activated by oxidative stress and up-regulates the downstream antioxidant enzymes, including -glutamylcysteine synthetase (-GCS), NAD(P)H dehydrogenase quinone 1 (NQO-1), and heme oxygenase-1 (HO-1) to protect cells from oxidative insult, we investigated the involvement of Nrf2 antioxidant system in cold exposure-induced neuroprotection. Results from time-course study revealed that cold exposure induced upregulation of nuclear Nrf2 protein and HO-1 mRNA (1 h), -GCS protein and HO-1 mRNA (6 h), HO-1 (12 h) and RBM3 (12-48 h) mRNA, and -GCS protein (24 h) and CIRBP mRNA and protein (24-48 h) expression. Cold exposure prevented MPP+-induced downregulation of CIRBP and-GCS and RNA binding motif 3 (RBM3, another cold-inducible protein), as well as upregulation of HO-1 and NQO-1 mRNA expression. Cold exposure can block MPP+-induced decrease in ARE promoter activity. CIRBP overexpression using cirbp-EGFP fusion protein plasmid or cotransfection cirbp/puromycin plasmid with ARE-pGL3 plasmid, but not transfection of cirbp/puromycin plasmid only, significantly reduced MPP+-induced neuron death, though a significant increase in H2O2 level was found. However, the effect of CIRBP overexpression on MPP+-induced changes in the expression of Nrf2-regulated antioxidant enzymes and its neuroprotective effect was less pronounced than that under cold exposure. We considered and examined whether the disparity was caused by the different distribution of CIRBP in cells. Results from immunocytochemistry and overexpression of cirbp-EGFP fusion protein studies showed that higher CIRBP expression was found in the nucleus than in the cytosol after MPP+ treatment and also in both cold exposure and CIRBP overexpression. These results imply that CIRBP plays partial role in cold exposure-induced neuroprotection.

Contents
中文摘要	1
Abstract	3
謝辭	5
Contents	7
Introduction	11
Parkinson’s disease (PD)	11
Clinical characteristics and pathological feature of Parkinson’s disease (PD)	11
MPTP/MPP+-induced parkinsonian model	12
Nrf2-regulated antioxidant defense system	12
The role of Nrf2 in neurodegenerative disease	13
Therapeutic hypothermia	14
Clinical application	14
Mechanisms underlying hypothermia-induced neuroprotection	14
Cold-inducible RNA binding protein (CIRBP)	15
Discovery of cold shock protein	15
The neuroprotective effect of CIRBP	16
The relationship between CIRBP and inflammatory	16
Research rationale and hypothesis	18
Specific aims	18
Materials and Methods	19
Chemicals and antibodies	19
Cell culture	19
3-[4, 5-Dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay	19
Propidium iodide (PI) staining	20
Determination of intracellular H2O2 level	20
Total RNA extraction	21
Reverse transcription-polymerase chain reaction (RT-PCR)	21
Isolation of nuclear extracts	22
Western blot analysis	23
Immunocytochemistry	23
Cloning of full length human CIRBP	24
Expression of the EGFP-CIRBP fusion protein	25
Transfection of FL-hCIRBP	25
Reporter assay	25
Statistical analysis	26
Results	27
Cold exposure prevents MPP+-induced cell death and H2O2 production 	27
Cold exposure upregulates the expression of CIRBP and Nrf2-regulated antioxidant enzymes 	27
Cold exposure prevents the effect of MPP+ on CIRBP, RBM3, and Nrf2-regulated gene expression	28
CIRBP overexpression prevents the MPP+-induced cell death, but induces a significant increase in H2O2 level	28
CIRBP translocates from the cytosol to the nucleus in cold exposure and CIRBP overexpression 	30
Discussion	31
Summary of our major findings	31
Brain temperature in Parkinson’s disease	31
The role of CIRBP on hypothermia against MPP+ toxicity	32
The role of CIRBP under various stresses	33
The effect of Nrf2-regulated antioxidant enzymes on hypothermia after MPP+ treatment	35
Conclusion	37
References	38
Figure contents	44
Figure 1  Protocol for cold exposure. 	44
Figure 2 Cold exposure prevents MPP+-induced cell death and H2O2 production. 	45
Figure 3 Cold exposure induces upregulation of CIRBP, HO-1 and RBM3 mRNA expression. 	46
Figure 4 Cold exposure induces increase in Nrf2, CIRBP, HO-1, and -GCSc protein expression. 	48
Figure 5 Cold exposure prevents MPP+-induced decrease in ARE promoter activity. 	49
Figure 6 Cold exposure inhibits MPP+-induced upregulation of HO-1 and NQO-1, and downregulation of CIRBP, -GCSc, and RBM3 mRNA expression. 	50
Figure 7 CIRBP overexpression induces H2O2 production and did not prevent MPP+-induced cell death. 	52
Figure 8 CIRBP overexpression did not mimic the effect of cold exposure on MPP+-induced gene expression. 	53
Figure 9 CIRBP overexpression prevents MPP+-induced decrease in ARE promoter activity. 	55
Figure 10 CIRBP overexpression prevents MPP+-induced cell death, but induces H2O2 production. 	56
Figure 11 Cold exposure and MPP+ induces CIRBP translocation to nucleus	57
Figure 12 CIRBP overexpression also induces CIRBP translocation to nucleus.	 	58
Figure 13 Overexpression of cirbp-EGFP fusion protein prevents basal and MPP+-induced cell death. 	59
Figure 14 Overexpression of cirbp-EGFP fusion protein represents CIRBP translocation to nucleus. 	60

                                    

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