本文選題：帕金森病 + 組蛋白去乙酰化酶�。� 參考：《華中科技大學(xué)》2016年博士論文

【摘要】：第一部分不同環(huán)境毒素誘導(dǎo)的PD細(xì)胞模型中HDAC亞型及PD相關(guān)重要分子變化目的研究PD環(huán)境毒素魚藤酮或甲氰菊酯對(duì)擬多巴胺能SH-SY5Y細(xì)胞系HDAC不同亞型及PD相關(guān)重要蛋白表達(dá)及定位的影響。方法魚藤酮或甲氰菊酯作用于SH-SY5Y細(xì)胞,采用Western blot或Real-time PCR方法了解環(huán)境毒素誘導(dǎo)的SH-SY5Y細(xì)胞模型中,HDAC1、HDAC4、HDAC6及PD標(biāo)志性病理蛋白α-突觸核蛋白(α-syn)的表達(dá)水平與處理時(shí)限或毒素濃度之間的關(guān)系；使用激光共聚焦顯微鏡觀察魚藤酮對(duì)HDAC不同亞型及α-syn定位及表達(dá)的影響。結(jié)果Western blot檢測(cè)發(fā)現(xiàn)魚藤酮處理可濃度依賴性及時(shí)間依賴性的誘發(fā)HDAC1、 HDAC4、HDAC6及α-syn蛋白表達(dá)增加,尤其寡聚體形式的α-syn增加明顯。Real-timePCR檢測(cè)表明,甲氰菊酯可濃度依賴性的誘發(fā)HDAC1、HDAC4、HDAC6和α-syn的mRNA水平升高,而多巴胺轉(zhuǎn)運(yùn)體(DAT)和囊泡單胺轉(zhuǎn)運(yùn)蛋白2(VMAT2)轉(zhuǎn)錄活性卻隨甲氰菊酯濃度增加呈現(xiàn)降低趨勢(shì)。激光共聚焦顯微鏡觀察發(fā)現(xiàn),隨著魚藤酮處理時(shí)間延長(zhǎng),胞核定位的HDAC1熒光強(qiáng)度逐漸增強(qiáng),并出現(xiàn)胞核內(nèi)異常聚集。正常細(xì)胞中HDAC4均勻彌散分布于胞漿內(nèi),胞核內(nèi)也有少量分布,魚藤酮干預(yù)后HDAC4熒光強(qiáng)度明顯增強(qiáng),并出現(xiàn)胞漿內(nèi)異常聚集以及胞核轉(zhuǎn)位增加,且HDAC4與α-syn共定位明顯。HDAC6與α-syn在正常細(xì)胞中彌散分布于細(xì)胞漿中,1μM魚藤酮處理48小時(shí)后,HDAC6與α-syn熒光強(qiáng)度明顯增強(qiáng),并出現(xiàn)胞漿內(nèi)異常聚集,HDAC6與α-syn蛋白共定位表達(dá)明顯。結(jié)論環(huán)境毒素魚藤酮或甲氰菊酯可誘導(dǎo)SH-SY5Y細(xì)胞中HDAC1、HDAC4、HDAC6及PD相關(guān)重要分子的表達(dá)及定位發(fā)生改變。第二部分不同環(huán)境毒素誘導(dǎo)的PD小鼠模型中HDAC亞型及PD相關(guān)重要分子變化目的研究PD環(huán)境毒素魚藤酮或甲氰菊酯對(duì)C57BL6/J小鼠黑質(zhì)區(qū)多巴胺能神經(jīng)元HDAC不同亞型及PD相關(guān)重要蛋白表達(dá)及定位的影響。方法將老年C57BL6/J小鼠隨機(jī)分為正常對(duì)照組和魚藤酮造模組,持續(xù)8周予以魚藤酮灌胃給藥(30mg/kg/d),建立穩(wěn)定可靠的PD小鼠模型,并采用激光共聚焦熒光顯微鏡觀察中腦黑質(zhì)致密區(qū)HDAC1、HDAC4、HDAC6以及a-syn、泛素的表達(dá)和定位變化。給予成年C57BL6/J小鼠腹腔注射甲氰菊酯,使用Real-time PCR方法檢測(cè)小鼠中腦黑質(zhì)區(qū)和紋狀體區(qū)HDAC1、HDAC4、HDAC6和PD相關(guān)重要分子的表達(dá)變化與毒素濃度或暴露時(shí)間之間的關(guān)系。結(jié)果激光共聚焦熒光顯微鏡檢測(cè)顯示,長(zhǎng)期慢性魚藤酮干預(yù)后,小鼠黑質(zhì)致密區(qū)多巴胺能神經(jīng)元胞核內(nèi)HDAC1表達(dá)較對(duì)照組明顯增多,HDAC4表達(dá)也明顯增加,部分細(xì)胞胞漿內(nèi)出現(xiàn)HDAC4染色陽(yáng)性的顆粒樣聚集體。正常老年小鼠中HDAC6彌散分布于黑質(zhì)多巴胺能神經(jīng)元胞漿和神經(jīng)突起中,慢性魚藤酮刺激后神經(jīng)元內(nèi)HDAC6表達(dá)明顯增多,神經(jīng)突起內(nèi)尤其明顯,部分神經(jīng)元胞漿內(nèi)蛋白聚集增加。我們還發(fā)現(xiàn),魚藤酮干預(yù)后多巴胺能神經(jīng)元胞漿和胞核中a-syn和泛素表達(dá)顯著增多,部分細(xì)胞內(nèi)出現(xiàn)a-syn或泛素染色陽(yáng)性的粗顆粒樣聚集。隨著甲氰菊酯濃度升高或暴露時(shí)間延長(zhǎng),中腦黑質(zhì)區(qū)a-syn轉(zhuǎn)錄活性呈增加趨勢(shì),而HDAC1、HDAC4、HDAC6以及DAT、 VMAT2的轉(zhuǎn)錄活性均呈下降趨勢(shì)。此外,紋狀體區(qū)DAT、VMAT2的轉(zhuǎn)錄活性也隨甲氰菊酯處理時(shí)間延長(zhǎng)逐漸降低。結(jié)論 環(huán)境毒素魚藤酮或甲氰菊酯干預(yù)可誘導(dǎo)小鼠多巴胺能神經(jīng)元中HDAC1、 HDAC4、HDAC6及PD相關(guān)重要分子的表達(dá)及定位發(fā)生改變。第三部分HDAC抑制劑對(duì)魚藤酮誘導(dǎo)的PD細(xì)胞模型的保護(hù)作用及相關(guān)機(jī)制目的探究不同HDAC抑制劑對(duì)魚藤酮誘導(dǎo)的PD細(xì)胞模型的保護(hù)作用及可能的相關(guān)機(jī)制。方法采用Western blot方法,檢測(cè)NaB或VPA對(duì)魚藤酮誘導(dǎo)的SH-SY5Y及SK-N-SH細(xì)胞模型中α-syn寡聚體以及磷酸化水平的影響,同時(shí)檢測(cè)自噬以及內(nèi)質(zhì)網(wǎng)應(yīng)激相關(guān)指標(biāo)的變化。并進(jìn)一步采用不同濃度的NaB或VPA預(yù)處理細(xì)胞,了解這兩種藥物對(duì)魚藤酮細(xì)胞模型的保護(hù)作用是否具有劑量依賴性。另外,分別使用3-MA或氯喹干擾自噬水平,Western blot檢測(cè)上述指標(biāo)變化,觀察NaB或VPA對(duì)魚藤酮誘導(dǎo)的PD細(xì)胞模型的影響。結(jié)果Western blot結(jié)果顯示,NaB或VPA預(yù)處理能夠明顯減少魚藤酮誘導(dǎo)的a-syn寡聚體和pSerl29 a-syn形成,同時(shí)上調(diào)Beclin 1表達(dá),促進(jìn)LC3-Ⅰ向LC3-Ⅱ轉(zhuǎn)化,增強(qiáng)自噬活性,促進(jìn)自噬流完成,并且減少魚藤酮誘發(fā)的內(nèi)質(zhì)網(wǎng)應(yīng)激對(duì)PD細(xì)胞模型發(fā)揮保護(hù)作用。這兩種藥物對(duì)魚藤酮細(xì)胞模型的保護(hù)效應(yīng)具有明顯的劑量依賴性。我們還發(fā)現(xiàn),NaB或VPA預(yù)處理上調(diào)LC3-Ⅱ表達(dá)這一效應(yīng)被自噬抑制劑3-MA削弱。使用氯喹可抑制自噬流完成,LC3-Ⅱ表達(dá)明顯增加,這一過程同樣減弱了NaB或VPA增強(qiáng)自噬的作用。另外,無論是否加入3-MA或氯喹,NaB或VPA干預(yù)均能減少SK-N-SH細(xì)胞內(nèi)pSer129 a-syn以及GRP78蛋白表達(dá)。結(jié)論NaB或VPA可通過增強(qiáng)自噬、促進(jìn)自噬流完成以及減少內(nèi)質(zhì)網(wǎng)應(yīng)激發(fā)揮對(duì)魚藤酮細(xì)胞模型的保護(hù)作用。第四部分HDAC抑制劑對(duì)慢性魚藤酮誘導(dǎo)的不同遺傳背景PD小鼠模型的保護(hù)作用及相關(guān)機(jī)制目的探索HDAC抑制劑對(duì)慢性魚藤酮誘導(dǎo)的不同遺傳背景PD小鼠模型的保護(hù)作用及相關(guān)機(jī)制。方法將老年野生型C57BL6/J小鼠隨機(jī)分為正常對(duì)照組、魚藤酮造模組、VPA+魚藤酮組以及NaB+魚藤酮組,老年VMAT2+/-或DAT+/-雜合子小鼠隨機(jī)分為溶劑對(duì)照組、魚藤酮造模組以及NaB+魚藤酮組,持續(xù)8周予以魚藤酮灌胃以及VPA/NaB腹腔注射。通過Rotarod及爬桿實(shí)驗(yàn)評(píng)定小鼠運(yùn)動(dòng)及協(xié)調(diào)能力；高效液相色譜-電化學(xué)法檢測(cè)小鼠紋狀體DA神經(jīng)遞質(zhì)含量；免疫組化、免疫熒光及Western blot檢測(cè)小鼠黑質(zhì)、紋狀體區(qū)PD相關(guān)重要蛋白的表達(dá)及定位變化；透射電鏡觀察小鼠黑質(zhì)和紋狀體區(qū)神經(jīng)元的超微結(jié)構(gòu)。結(jié)果 慢性魚藤酮干預(yù)后不同遺傳背景的小鼠較溶劑對(duì)照組爬桿時(shí)間明顯延長(zhǎng),Rotarod潛伏時(shí)間縮短,其中VMAT2+/-、鼠運(yùn)動(dòng)功能減退較野生型小鼠更加顯著,DAT+/-小鼠運(yùn)動(dòng)功能減退則不如野生型顯著,而NaB或VPA預(yù)處理在3種基因型小鼠中均顯著改善了魚藤酮所致的運(yùn)動(dòng)功能損傷。高效液相色譜檢測(cè)顯示,NaB預(yù)處理均顯著增加了3種基因型小鼠紋狀體DA的含量。腦組織切片免疫組化及免疫熒光激光共聚焦檢測(cè)顯示,在野生型、VMAT2+/-和DAT+/-小鼠中,NaB或VPA預(yù)處理能部分逆轉(zhuǎn)慢性魚藤酮暴露所致的黑質(zhì)致密部TH陽(yáng)性神經(jīng)元數(shù)目的減少,減輕黑質(zhì)DA神經(jīng)元和海馬神經(jīng)元內(nèi)α-syn或泛素陽(yáng)性的蛋白聚集,還能明顯減少魚藤酮引起的P62陽(yáng)性顆粒樣聚集物增多。Westem blot結(jié)果表明慢性魚藤酮刺激后LC3-Ⅱ和P62蛋白水平增加,自噬流受阻,而NaB或VPA預(yù)處理通過增加LC3-Ⅱ表達(dá),降低P62蛋白水平從而促進(jìn)自噬流完成。透射電鏡結(jié)果顯示,慢性魚藤酮干預(yù)后野生型及DAT+/-小鼠黑質(zhì)區(qū)和紋狀體區(qū)線粒體腫脹明顯,部分線粒體嵴消失,甚至空泡化；NaB預(yù)處理可明顯減輕魚藤酮所致的線粒體損傷,并增加自噬液泡數(shù)量,尤其自噬溶酶體數(shù)目增加明顯。結(jié)論HDAC抑制劑NaB通過增強(qiáng)自噬活性對(duì)慢性魚藤酮誘導(dǎo)的不同遺傳背景小鼠的黑質(zhì)紋狀體系統(tǒng)損傷具有明顯的神經(jīng)保護(hù)作用。
[Abstract]:The effects of PD environmental toxin rotenone or fenprothrin on the expression and localization of the different subtypes of HDAC and PD related important proteins in the pseudo dopaminergic SH-SY5Y cell line and the effect of PD on the expression and localization of PD related important proteins in the PD cell model of different environmental toxin induced PD cell models. To understand the relationship between the expression level of HDAC1, HDAC4, HDAC6 and PD ICP - alpha synuclein (alpha -syn) in the SH-SY5Y cell model induced by environmental toxins by Western blot or Real-time PCR, and the relationship between the time limit of treatment and the concentration of toxin; using laser confocal microscopy to observe the localization of rotenone to HDAC subtypes and alpha -syn Results Western blot detection found that rotenone treated the concentration dependent and time dependent induced HDAC1, HDAC4, HDAC6 and alpha -syn protein expression increased, especially in the oligomer form of alpha -syn, and the obvious.Real-timePCR detection showed that the concentration of pyrethrin could induce HDAC1, HDAC4, HDAC6 and alpha -syn. The transcriptional activity of the dopamine transporter (DAT) and the vesicle monoamine transporter 2 (VMAT2) decreased with the increase of the concentration of pyrethrin. The laser confocal microscope observed that the HDAC1 fluorescence intensity of the nucleus localization gradually increased with the prolonged treatment of rotenone, and the abnormal aggregation of the nucleus in the nucleus. HDAC4 in normal cells. The uniform dispersion was distributed in the cytoplasm, and there was a small amount of distribution in the nucleus. The intensity of HDAC4 fluorescence was obviously enhanced after rotenone, and the abnormal aggregation of the cytoplasm and the transposition of the nucleus appeared in the cytoplasm, and the HDAC4 and the alpha -syn were conformed with the obvious.HDAC6 and the alpha -syn in the normal cells and distributed in the cytoplasm. After 48 hours treatment of 1 UG, HDAC6 and alpha -sy were found. The fluorescence intensity of N was obviously enhanced and abnormal aggregation in the cytoplasm was found, and the expression of HDAC6 and alpha -syn protein was obvious. Conclusion the expression and localization of HDAC1, HDAC4, HDAC6 and PD related important molecules in SH-SY5Y cells can be induced by environmental toxin rotenone or fenpromethrin. HDAC in the PD mouse model induced by second different environmental toxins. Objective to study the effects of subtype and PD related important molecular changes in PD environmental toxin rotenone or fenprothrin on the expression and localization of HDAC different subtypes of dopaminergic neurons in the substantia nigra area of C57BL6/J mice and the expression and location of PD related important proteins. Methods the aged C57BL6/J mice were randomly divided into normal control group and To module, and continued to use rotenone for 8 weeks. A stable and reliable PD mouse model was established by intragastric administration (30mg/kg/d). The expression and localization of ubiquitin, HDAC1, HDAC4, HDAC6 and a-syn in the mesencephalic dense region were observed by laser confocal fluorescence microscopy. The intraperitoneal injection of fenpromethrin in adult C57BL6/J mice was given and Real-time PCR method was used to detect the black mass and striatum in the midbrain of mice. The relationship between the expression changes of HDAC1, HDAC4, HDAC6 and PD related important molecules with the concentration of toxin and the time of exposure. Results the laser confocal fluorescence microscopy showed that the prognosis of chronic rotenone showed that the HDAC1 table in the nucleus of dopaminergic neurons in the dense area of the murine substantia nigra was significantly increased, and the expression of HDAC4 increased obviously. In addition, in the cytoplasm of some cells, HDAC4 staining positive particle aggregates were found. In normal aged mice, HDAC6 dispersion was distributed in the cytoplasm and neurites of dopaminergic neurons in the substantia nigra. The expression of HDAC6 in neurons increased significantly in neurons after chronic rotenone stimulation, especially in the neurites, and the accumulation of protein in the cytoplasm of some neurons increased. We also found that after the intervention of rotenone, the expression of a-syn and ubiquitin in the cytoplasm and nucleus of dopaminergic neurons increased significantly. In some cells, there were a-syn or ubiquitin positive coarse particle like aggregation. With the increase of the concentration of methrin or the prolonged exposure time, the activity of a-syn transcriptional activity in the mesencephalic substantia nigra increased, while HDAC1, HDAC4, HDAC6 and D were increased. The transcriptional activity of AT and VMAT2 decreased. In addition, the transcriptional activity of DAT and VMAT2 in the striatum also gradually decreased with the prolongation of the time of methrin treatment. Conclusion the intervention of rotenone or pyrethrin can induce the expression and localization of HDAC1, HDAC4, HDAC6 and PD related important molecules in the dopaminergic neurons of mice. The three part of the protective effect of HDAC inhibitor on rotenone induced PD cell model and related mechanisms to explore the protective effect and possible mechanism of different HDAC inhibitors on rotenone induced PD cell model. Methods the Western blot method was used to detect the alpha -syn in the SH-SY5Y and SK-N-SH cell models induced by rotenone by NaB or VPA. The effects of oligomers and phosphorylation levels, and the changes in autophagy and endoplasmic reticulum stress related indicators, and the further use of different concentrations of NaB or VPA pretreated cells to understand whether the protective effects of these two drugs on rotenone cell model are dose-dependent. Furthermore, the use of 3-MA or chloroquine to interfere with autophagy, W Estern blot detected the changes of the above indexes and observed the effects of NaB or VPA on the PD cell model induced by rotenone. Results Western blot results showed that NaB or VPA pretreatment could significantly reduce the formation of a-syn oligomer and pSerl29 a-syn induced by rotenone, and up up the expression of 1. The autophagic flow was completed and the rotenone induced endoplasmic reticulum stress was protected against the PD cell model. The protective effects of these two drugs on the rotenone cell model were significantly dose-dependent. We also found that the effect of NaB or VPA preconditioning on the expression of LC3- II was weakened by the autophagic inhibitor 3-MA. Chloroquine was inhibited. The expression of autophagic flow was completed, the expression of LC3- II increased significantly. This process also weakened the role of NaB or VPA to enhance autophagy. In addition, the NaB or VPA intervention could reduce the pSer129 a-syn and GRP78 protein expression in SK-N-SH cells whether or not 3-MA or chloroquine. Conclusion NaB or VPA can enhance autophagy, promote autophagy completion and reduce endoplasmic reticulum. The protective effect of the net on rotenone cell model. Fourth the protective effect of HDAC inhibitor on the different genetic background PD mice induced by chronic rotenone and the related mechanisms to explore the protective effect and mechanism of HDAC inhibitors on different genetic background PD mice induced by chronic rotenone. The wild type C57BL6/J mice were randomly divided into normal control group, To module, VPA+ rotenone group and NaB+ rotenone group. The aged VMAT2+/- or DAT+/- heterozygote mice were randomly divided into the solvent control group, the To module and the NaB+ rotenone group, which lasted for 8 weeks with rotenone gavage and VPA/NaB intraperitoneal injection. Through Rotarod and climbing pole real. The activity and coordination ability of mice were evaluated and the content of DA neurotransmitter in mice striatum was detected by high performance liquid chromatography electrochemistry; immunohistochemistry, immunofluorescence and Western blot were used to detect murine substantia nigra, expression and localization of PD related proteins in striatum; ultrastructure of neurons in substantia nigra and striatum of mice was observed by transmission electron microscopy Results in mice with different genetic background, the climbing pole time of the mice with different genetic background was significantly longer than that of the solvent control group, and the latency of Rotarod was shortened, in which VMAT2+/-, the motor function decreased more significantly in mice than in the wild type mice, and the decrease of motor function in DAT+/- mice was not as significant as that of the wild type, while the NaB or VPA pretreatment was in 3 genotypic mice. The motor function damage caused by rotenone was significantly improved. High performance liquid chromatography (HPLC) showed that NaB preconditioning significantly increased the content of DA in the striatum of 3 genotypes. Immunohistochemistry of brain tissue and confocal immunofluorescence laser confocal microscopy showed that NaB or VPA pretreatment could be partially reversed in wild type, VMAT2+/- and DAT+/- mice. The number of TH positive neurons in the dense part of substantia nigra caused by chronic rotenone exposure decreased, alleviated the aggregation of alpha -syn or ubiquitin positive protein in DA neurons and hippocampal neurons, and significantly reduced the increase of P62 positive particles like aggregates caused by rotenone,.Westem blot results indicated that chronic rotenone stimulated LC3- II and P62 protein water. In addition, autophagic flow was hindered, while NaB or VPA preconditioning could promote autophagic flow by increasing LC3- II expression, reducing P62 protein level and promoting autophagic flow. The transmission electron microscopy showed that the mitochondria swelling in the substantia nigra and striatum of the wild type and DAT+/- mice was obvious, and the mitochondrial crista disappeared and even vacuolated, and NaB preconditioning could be used for the transmission electron microscope. The number of autophagic vacuoles increased significantly, especially the number of autophagic lysosomes increased obviously. Conclusion the HDAC inhibitor NaB has a clear neuroprotective effect on the nigrostriatal system damage in mice with different genetic background induced by chronic rotenone.
【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R742.5

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