本文關(guān)鍵詞： 帕金森病 MPP~+/MPTP 內(nèi)質(zhì)網(wǎng)應(yīng)激 硫氧還蛋白 分子機(jī)理　出處：《昆明理工大學(xué)》2014年博士論文　論文類型：學(xué)位論文

【摘要】：帕金森病(Parkinson's disease, PD)是一種常見(jiàn)的神經(jīng)退行性疾病,其病理特征是中腦黑質(zhì)區(qū)(substantia nigra pars compacta, SNpc)多巴胺能神經(jīng)元進(jìn)行性變性壞死,導(dǎo)致多巴胺水平降低。PD的分子機(jī)制已經(jīng)被廣泛的研究,然而仍不清楚。 大量的研究表明氧化應(yīng)激(oxidative stress)和內(nèi)質(zhì)網(wǎng)應(yīng)激(endoplasmic reticulum stress, ER stress)與PD的發(fā)病機(jī)理有關(guān)。未折疊蛋白在內(nèi)質(zhì)網(wǎng)的積累激活了通路蛋白的轉(zhuǎn)錄即未折疊蛋白應(yīng)答(unfolded protein response, UPR)。內(nèi)質(zhì)網(wǎng)應(yīng)激引發(fā)兩個(gè)細(xì)胞保護(hù)應(yīng)答反應(yīng),一方面是減少蛋白質(zhì)的合成,另一方面是促進(jìn)蛋白質(zhì)折疊分子伴侶基因的表達(dá)上調(diào)。UPR的主要信號(hào)通路包括：(1)肌醇需求酶1(inositol-requiring enzyme1, IRE1)活化拼接X(jué)-box結(jié)合蛋白1(X-box binding protein1, XBP1)的mRNA;(2)活化轉(zhuǎn)錄因子(activating transcription factor6, ATF6)從內(nèi)質(zhì)網(wǎng)釋放,活化后進(jìn)入細(xì)胞核上調(diào)內(nèi)質(zhì)網(wǎng)應(yīng)答相關(guān)基因轉(zhuǎn)錄水平；(3)蛋白激酶RNA樣內(nèi)質(zhì)網(wǎng)激酶(protein kinase RNA-like ER kinase, PERK)活化使真核生物翻譯起始因子2a(eukaryotic translation initiation factor2a, eIF2a)發(fā)生磷酸化,導(dǎo)致翻譯起始抑制。如果內(nèi)質(zhì)網(wǎng)應(yīng)激持續(xù)時(shí)間過(guò)長(zhǎng),UPR就會(huì)引發(fā)末期事件,如內(nèi)質(zhì)網(wǎng)Ca2+釋放以及促凋亡通路的活化,包括腫瘤壞死因子受體相關(guān)因子2(tumor necrosis factor receptor associated factor2,TRAF2)、凋亡信號(hào)調(diào)節(jié)激酶1(apoptosis signal regulating kinase1, ASK1)和c-jun N-末端激酶(c-jun N-terminal kinase, JNK),最終導(dǎo)致細(xì)胞死亡。 硫氧還蛋白-1(Thioredoxin-1, Trx-1)是一個(gè)12kDa的多功能蛋白,含有一個(gè)保守的活性位點(diǎn)序列：-Cys-Gly-Pro-Cys-。越來(lái)越多的研究表明Trx-1可以抵抗細(xì)胞損傷和環(huán)境應(yīng)激而起細(xì)胞保護(hù)作用。Trx-1能夠清除單氧自由基和羥自由基。Trx-1可以保護(hù)細(xì)胞免于過(guò)氧化氫(hydrogen peroxide, H2O2)、紫外線照射和局部腦缺血引起的損傷。我們以前的研究表明MPP+處理大鼠腎上腺嗜鉻細(xì)胞瘤PC12細(xì)胞顯著降低Trx-1的表達(dá),并且Trx-1高表達(dá)減輕了MPP+誘導(dǎo)的神經(jīng)毒性,Trx-1高表達(dá)抑制內(nèi)質(zhì)網(wǎng)凋亡分子caspase12的表達(dá),然而它們的分子機(jī)制仍不清楚。 帕金森病毒性化合物1-甲基-4-苯基-1,2,3,6-四氫吡啶(1-Methy-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP)及其活性代謝物1-甲基-4-苯基吡啶離子(1-methyl-4-phenylpyridinium ion, MPP+)常被用來(lái)構(gòu)建PD體內(nèi)和體外的實(shí)驗(yàn)?zāi)Ｐ汀?在本論文中,我們研究了MPP+處理PC12細(xì)胞對(duì)葡萄糖調(diào)節(jié)蛋白78(Glucose Regulated Protein78, GRP78)、IRE1α、TRAF2、C/EBP同源蛋白(C/EBP homologous protein, CHOP)、含半胱氨酸的天冬氨酸蛋白水解酶原12(pro-cysteinyl aspartate specific proteinase-12, procaspase-12)和JNK表達(dá)的影響。我們還進(jìn)一步研究了Trx-1對(duì)GRP78、IRE1α、TRAF2、 CHOP、procaspase-12和JNK的調(diào)節(jié)作用。本論文的主要研究結(jié)果如下： (1)MPP+誘導(dǎo)PC12細(xì)胞發(fā)生內(nèi)質(zhì)網(wǎng)應(yīng)激。0.3mM的MPP+處理PC12細(xì)胞不同的時(shí)間(0、2、6、12和24h或0、15、30、45和60min)后,用Western Blot檢測(cè)MPP+對(duì)GRP78、 IRE1α、TRAF2、CHOP、procaspase-12和JNK表達(dá)的影響。結(jié)果顯示MPP+以時(shí)間依賴的方式誘導(dǎo)GRP78、IRE1α、TRAF2和CHOP的表達(dá)和procaspase-12的切割活化,MPP+處理在很短的時(shí)間內(nèi)就活化了JNK。為了確認(rèn)ER凋亡途徑的執(zhí)行者procaspase-12是否是被JNK活化,用JNK的抑制劑SP600125預(yù)處理PC12細(xì)胞30min,再用MPP+刺激24h,結(jié)果顯示procaspase-12的活化被SP600125抑制。 (2)Trx-1調(diào)節(jié)MPP+誘導(dǎo)的細(xì)胞毒性。MPP+處理顯著降低了PC12細(xì)胞的存活率,MPP+以時(shí)間依賴的方式降低PC12細(xì)胞中Trx-1的表達(dá),且MPTP降低野生型C57BL/6小鼠SNpc區(qū)Trx-1的表達(dá)。為闡明Trx-1是否在抑制MPP+毒性中起重要作用,轉(zhuǎn)染siRNA降低Trx-1表達(dá)或轉(zhuǎn)染GFP-Trx-1質(zhì)粒使Trx-1高表達(dá),用MTT分析檢測(cè)Trx-1低表達(dá)或高表達(dá)對(duì)MPP+毒性作用的影響。轉(zhuǎn)染Trx-1siRNA或GFP-human Trx-1質(zhì)粒對(duì)PC12細(xì)胞無(wú)明顯的細(xì)胞毒性。Trx-1表達(dá)下調(diào)增加了PC12細(xì)胞對(duì)MPP+誘導(dǎo)毒性的敏感性。相反,Trx-1高表達(dá)抑制了MPP+誘導(dǎo)的細(xì)胞毒性。這些結(jié)果表明Trx-1在MPP+誘導(dǎo)的細(xì)胞毒性中起重要的調(diào)節(jié)作用。 (3)Trx-1低表達(dá)加重MPP+誘導(dǎo)的內(nèi)質(zhì)網(wǎng)應(yīng)激。PC12細(xì)胞轉(zhuǎn)染Trx-1siRNA24h, MPP+刺激24h或15min,我們研究了Trx-1表達(dá)下調(diào)對(duì)MPP+誘導(dǎo)的內(nèi)質(zhì)網(wǎng)應(yīng)激的影響。Trx-1敲低后MPP+誘導(dǎo)的GRP78表達(dá)進(jìn)一步增加,表明Trx-1siRNA加重了MPP+誘導(dǎo)的內(nèi)質(zhì)網(wǎng)應(yīng)激。我們也檢測(cè)了Trx-1siRNA對(duì)IRE1α、TRAF2、CHOP、JNK和procaspase-12的影響。Trx-1siRNA進(jìn)一步增加了MPP+誘導(dǎo)的IRE1α、TRAF2和CHOP的表達(dá)以及JNK和procaspase-12的活化。這些結(jié)果表明Trx-1siRNA通過(guò)增加IRE1α、TRAF2和CHOP的表達(dá)以及活化JNK和procaspase-12，，加重MPP+誘導(dǎo)的內(nèi)質(zhì)網(wǎng)應(yīng)激。 (4)Trx-1高表達(dá)減輕MPP+誘導(dǎo)的內(nèi)質(zhì)網(wǎng)應(yīng)激。PC12細(xì)胞轉(zhuǎn)染GFP-human Trx-1質(zhì)粒高表達(dá)Trx-1,然后檢測(cè)Trx-1高表達(dá)對(duì)MPP+誘導(dǎo)的內(nèi)質(zhì)網(wǎng)應(yīng)激的影響。結(jié)果顯示Trx-1高表達(dá)抑制了MPP+誘導(dǎo)的GRP78表達(dá)增加。而且MPP+誘導(dǎo)的IRE1α、TRAF2和CHOP的表達(dá)以及JNK和procaspase-12的活化也被Trx-1高表達(dá)抑制。這些數(shù)據(jù)表明Trx-1高表達(dá)通過(guò)抑制IRE1α、TRAF2和CHOP的表達(dá),以及減少JNK和procaspase-12的活化,從而減輕了MPP+誘導(dǎo)的內(nèi)質(zhì)網(wǎng)應(yīng)激。 (5)Trx-1抑制MPTP誘導(dǎo)的內(nèi)質(zhì)網(wǎng)應(yīng)激。我們檢測(cè)了Trx-1是否能在小鼠模型抑制MPTP誘導(dǎo)的毒性。野生型MPTP組和human Trx-1轉(zhuǎn)基因MPTP組小鼠腹腔注射MPTP(20mg/kg,每天2次,注射7天),野生型對(duì)照組和human Trx-1轉(zhuǎn)基因?qū)φ战M小鼠注射等體積的生理鹽水。野生型MPTP組小鼠與野生型對(duì)照組相比運(yùn)動(dòng)能力顯著降低,而human Trx-1轉(zhuǎn)基因MPTP組小鼠與hTrx-1轉(zhuǎn)基因?qū)φ战M相比運(yùn)動(dòng)能力沒(méi)有降低。在本論文中,我們還檢測(cè)了Trx-1對(duì)MPTP引起的肢體運(yùn)動(dòng)損傷的影響。實(shí)驗(yàn)結(jié)果顯示Trx-1高表達(dá)改善了MPTP誘導(dǎo)的肢體損傷。為評(píng)估多巴胺能神經(jīng)元的丟失,我們用免疫組織化學(xué)和Western Blot分析檢測(cè)了小鼠SNpc區(qū)酪氨酸羥化酶(tyrosine hydroxylase, TH)的表達(dá)情況。MPTP處理后,野生型小鼠黑質(zhì)區(qū)TH表達(dá)顯著降低,而轉(zhuǎn)基因小鼠中Trx-1高表達(dá)回復(fù)了TH表達(dá)。這些數(shù)據(jù)表明Trx-1高表達(dá)保護(hù)多巴胺能神經(jīng)元免于MPTP誘導(dǎo)的神經(jīng)毒性損傷。與PC12細(xì)胞內(nèi)結(jié)果一致,在轉(zhuǎn)基因小鼠中Trx-1高表達(dá)顯著抑制了黑質(zhì)區(qū)GRP78表達(dá)的增加,表明Trx-1高表達(dá)減輕了MPTP誘導(dǎo)的內(nèi)質(zhì)網(wǎng)應(yīng)激。并且Trx-1高表達(dá)抑制了MPTP誘導(dǎo)的IRE1α、TRAF2和CHOP的表達(dá)以及JNK和procaspase-12的活化。這些數(shù)據(jù)表明Trx-1高表達(dá)通過(guò)抑制IRE1α、 TRAF2和CHOP的表達(dá),以及JNK和procaspase-12的活化,從而抑制了MPTP的神經(jīng)毒性。 在本論文中,我們系統(tǒng)地在體外和體內(nèi)研究了Trx-1抑制MPP+/MPTP誘導(dǎo)的內(nèi)質(zhì)網(wǎng)應(yīng)激的分子機(jī)制。從實(shí)驗(yàn)結(jié)果我們得出結(jié)論：Trx-1在帕金森病中通過(guò)抑制IRE1α、TRAF2、CHOP、JNK和procaspase-12的活化,抑制了內(nèi)質(zhì)網(wǎng)應(yīng)激,從而發(fā)揮神經(jīng)保護(hù)功能。
[Abstract]:Parkinson's disease (Parkinson's disease PD) is a common neurodegenerative disease, the pathological feature of midbrain substantia nigra (substantia nigra pars compacta, SNpc) of dopaminergic neurons degeneration and necrosis, resulting in decreased levels of dopamine.PD molecular mechanism has been extensively studied, however, is still not clear.
A large number of studies show that oxidative stress (oxidative stress) and endoplasmic reticulum stress (endoplasmic reticulum stress, ER stress) associated with the pathogenesis of PD. The unfolded protein in the endoplasmic reticulum activates transcription pathway protein accumulation of unfolded protein response (unfolded protein, response, UPR). The endoplasmic reticulum stress triggered two cell protection in response, one is to reduce the protein synthesis, on the other hand is the main pathway to promote the expression of.UPR protein folding molecular chaperone genes include: (1) 1 (inositol-requiring enzyme1 inositol requiring enzyme, IRE1) activated splicing X-box binding protein 1 (X-box binding protein1, XBP1 mRNA); (2) activation transcription factors (activating transcription factor6, ATF6) release from the endoplasmic reticulum, endoplasmic reticulum increased into the nucleus after activation response related gene transcription level; (3) like protein kinase RNA Er kinase (protein kinase RNA-like ER kinase, PERK) activation of the eukaryotic translation initiation factor 2A (eukaryotic translation initiation factor2a, eIF2a) phosphorylation, resulting in inhibition of translation initiation. If ER stress lasts for a long time, UPR will lead to the end of the event, such as the activation of endoplasmic reticulum Ca2+ release and apoptosis pathway, including tumor necrosis factor receptor associated factor 2 (tumor necrosis factor receptor associated FACTOR2, TRAF2), apoptosis signal regulating kinase 1 (apoptosis signal regulating kinase1, ASK1) and c-jun (c-Jun N-terminal kinase N- terminal kinase, JNK), eventually leading to cell death.
Thioredoxin -1 (Thioredoxin-1, Trx-1) is a multifunctional protein 12kDa, containing a conserved active site sequence: -Cys-Gly-Pro-Cys-. an increasing number of studies show that Trx-1 can resist cell damage and environmental stress and cell protective effect of.Trx-1 can remove singlet oxygen and hydroxyl radical.Trx-1 can protect cells from hydrogen peroxide (hydrogen peroxide, H2O2), caused by ultraviolet irradiation and local cerebral ischemia injury. Our previous study showed that MPP+ treatment of rat pheochromocytoma PC12 cells significantly decreased Trx-1 expression and high expression of Trx-1 reduces MPP+ induced neurotoxicity, high expression of Trx-1 inhibits the expression of endoplasmic reticulum apoptosis caspase12, however, their molecular mechanisms is still not clear.
Parkinson viral compounds 1- methyl -4- phenyl -1,2,3,6- tetrahydropyridine four (1-Methy-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP) and its active metabolite 1- methyl -4- phenyl pyridine ion (1-methyl-4-phenylpyridinium ion MPP+) is often used to construct the experimental model of PD in vivo and in vitro.
In this paper, we study the MPP+ treatment of PC12 cells to glucose regulated protein 78 (Glucose Regulated, Protein78, GRP78), IRE1 alpha, TRAF2, C/EBP (C/EBP homologous protein homologous protein, CHOP), containing cysteine aspartic acid proteolytic zymogens 12 (pro-cysteinyl aspartate specific proteinase-12, procaspase-12 and JNK) on the expression of we further studied the Trx-1 of GRP78, TRAF2, IRE1 alpha, CHOP, regulation of procaspase-12 and JNK. The main results are as follows:
(1) PC12 cells to endoplasmic reticulum stress induced by.0.3mM MPP+ MPP+ in PC12 cells treated with different time (0,2,6,12 and 24h or 0,15,30,45 and 60min), Western Blot detection of MPP+ on GRP78, TRAF2, CHOP, IRE1 alpha, procaspase-12 expression and JNK. The results showed that MPP+ induced by GRP78 in a time-dependent manner. IRE1 alpha, procaspase-12 and the expression of TRAF2 and cleavage of CHOP activation, MPP+ treatment in a very short period of time in order to confirm the activation of JNK. ER apoptosis pathway executive procaspase-12 is activated by JNK, with SP600125 JNK inhibitor pretreatment PC12 30min cell stimulation with MPP+ 24h, the results showed that procaspase-12 activation is the inhibition of SP600125.
(2) Trx-1 in the regulation of cell toxicity of.MPP+ induced by MPP+ treatment significantly reduced the survival rate of PC12 cells in a time-dependent manner, MPP+ reduced the expression of Trx-1 in PC12 cells, and MPTP reduced Trx-1 expression in wild-type C57BL/6 mice SNpc. To clarify whether Trx-1 plays an important role in inhibiting the toxicity of MPP+, transfection of siRNA decreased the expression of Trx-1 or GFP-Trx-1 plasmid was transfected into the high expression of Trx-1, Trx-1 expression analysis of low or high toxicity effect on the expression of MPP+ with MTT Trx-1siRNA or GFP-human Trx-1 plasmid. Transfection of PC12 cells without cytotoxicity.Trx-1 expression significantly increased the sensitivity of PC12 cells to MPP+ induced toxicity. On the contrary, the high expression of Trx-1 inhibits cell the toxicity induced by MPP+. These results suggest that Trx-1 may play an important role in MPP+ induced cytotoxicity.
(3) the low expression of Trx-1 increased MPP+ induced endoplasmic reticulum stress in.PC12 cells transfected with Trx-1siRNA24h, 24h or 15min MPP+ stimulation, we studied the effect of down-regulation of Trx-1 expression of endoplasmic reticulum stress induced by MPP+.Trx-1 on MPP+ induced by low GRP78 expression after further increase showed that Trx-1siRNA increased the endoplasmic reticulum stress induced by MPP+. We also detection of Trx-1siRNA on IRE1 alpha, TRAF2, CHOP, JNK and procaspase-12.Trx-1siRNA further increased MPP+ induced IRE1 alpha, TRAF2 and the expression of CHOP and JNK and the activation of procaspase-12. That Trx-1siRNA by increasing the IRE1 alpha of these results, the expression of TRAF2 and CHOP and activation of JNK and procaspase-12, increased endoplasmic reticulum stress MPP+ induced.
(4) the high expression of Trx-1 reduced MPP+ induced endoplasmic reticulum stress in.PC12 cells transfected with GFP-human plasmid Trx-1 with high expression of Trx-1, then detect the effect of Trx-1 overexpression on the endoplasmic reticulum stress induced by MPP+. The results showed that high expression of Trx-1 inhibited MPP+ induced increased expression of GRP78. MPP+ and IRE1 induced by alpha, TRAF2 and CHOP expression and the activation of JNK and procaspase-12 were high expression of Trx-1 inhibited. These data suggest that high expression of Trx-1 by inhibiting IRE1 alpha, expression of TRAF2 and CHOP, and reduce the activation of JNK and procaspase-12, thus reducing endoplasmic reticulum stress induced by MPP+.
(5) Trx-1 inhibition of endoplasmic reticulum stress induced by MPTP. We examined whether Trx-1 can inhibit MPTP induced toxicity in mice. Wild type MPTP group and human Trx-1 transgenic mice were intraperitoneally injected with MPTP MPTP (20mg/kg, 2 times daily injections for 7 days), the wild type control saline group and human transgenic Trx-1 mice injected with wild-type MPTP. Mice and wild type compared to the control group exercise capacity decreased significantly, while the human Trx-1 transgenic mice in group MPTP and hTrx-1 transgenic compared to the control group, exercise capacity did not decrease. In this thesis, we also examined the effect of Trx-1 on MPTP induced limb injury. Experimental results show that the high expression of Trx-1 improved limb injury induced by MPTP. In order to evaluate the loss of dopaminergic neurons, we examined mice SNpc tyrosine hydroxylase immunohistochemistry and Western Blot analysis (TY Rosine hydroxylase, TH) expression after.MPTP treatment, the expression of wild type mice substantia nigra TH decreased significantly, and the high expression of Trx-1 in transgenic mice responded to TH expression. These data suggest that overexpression of Trx-1 protects dopaminergic neurons from MPTP induced neurotoxicity in PC12 cells. And the results are consistent, high Trx-1 in transgenic mice the expression increased significantly inhibited the expression of GRP78 in substantia nigra, showed high expression of Trx-1 reduces endoplasmic reticulum stress induced by MPTP. And the high expression of Trx-1 inhibited MPTP induced IRE1 alpha, TRAF2 and the expression of CHOP and JNK and the activation of procaspase-12. These data suggest that the high expression of Trx-1 by inhibiting the expression of TRAF2 and IRE1 alpha. CHOP, and the activation of JNK and procaspase-12, thus inhibiting the neurotoxicity of MPTP.
In this paper, the molecular mechanism of endoplasmic reticulum stress we systematically investigated in vitro and in vivo inhibition of Trx-1 induced by MPP+/MPTP. From the experimental results, we can draw a conclusion: Trx-1 by inhibiting IRE1 alpha, in Parkinson's disease TRAF2, CHOP, JNK and procaspase-12 activation, inhibition of endoplasmic reticulum stress, and thus play a neuroprotective function.

【學(xué)位授予單位】：昆明理工大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R742.5;R-332

【共引文獻(xiàn)】

相關(guān)期刊論文 前10條

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