SIRT1在帕金森病中的研究進(jìn)展

朱朝娟，王倩梅，梁 赫，劉思達(dá)，馬 軒，梁 業(yè)，梁逸飛

SIRT1在帕金森病中的研究進(jìn)展

朱朝娟，王倩梅，梁 赫，劉思達(dá)，馬 軒，梁 業(yè)，梁逸飛

帕金森??；沉默信息調(diào)控因子1；治療

沉默信息調(diào)控因子1(silence information regulator 1, SIRT1)是Sirtuins家族中的一員，在煙酰胺腺苷二核苷酸(NAD+)存在的情況下具有組蛋白脫乙?；傅淖饔?。帕金森病(Parkinson's disease, PD)是一種進(jìn)行性中樞神經(jīng)系統(tǒng)退行性疾病，因腦黑質(zhì)多巴胺能(dopamine, DA)神經(jīng)元進(jìn)行性減少，對肌肉運(yùn)動(dòng)的抑制減弱，出現(xiàn)不自主震顫、肌肉強(qiáng)直收縮和姿勢反射障礙等癥狀[1-2]。流行病學(xué)調(diào)查顯示，美國約有60萬PD患者，且發(fā)病率呈逐漸上升趨勢[3-4]。近年研究發(fā)現(xiàn)SIRT1具有改善PD的作用[5-6]。本文通過對SIRT1與PD相關(guān)研究的回顧，探討SIRT1相關(guān)藥物在PD治療中的可行性。

1 SIRT1概述

SIRT1在NAD+存在的情況下發(fā)揮組蛋白脫乙?；傅淖饔?，調(diào)控轉(zhuǎn)錄后翻譯，調(diào)節(jié)正常神經(jīng)元的生理功能、促進(jìn)突觸形成及維持重塑能力，限制能量代謝和延長壽命，故亦稱為“長壽蛋白”[7]。SIRT1的NAD+依賴的脫乙?；缸饔猛ㄟ^激活過氧化物酶體增殖物激活受體γ輔激活因子1α(peroxisomal proliferator-activated receptor-coactivator1α, PGC-1α)，發(fā)揮抗氧化、應(yīng)激防御和保護(hù)線粒體的作用[8]；通過活化腺苷酸活化蛋白激酶(AMP-activated protein kinase, AMPK)發(fā)揮自噬作用以清除異常蛋白[9]；通過對NF-κB脫乙?；饔媒档推滢D(zhuǎn)錄活性，抑制誘導(dǎo)型氧化氮合酶(iNOS)表達(dá)，降低腫瘤壞死因子-α(TNF-α)和白細(xì)胞介素-6(IL-6)的表達(dá)從而抑制神經(jīng)炎癥[5]。SIRT1主要激動(dòng)劑為白藜蘆醇，一種化學(xué)名為3，5，4'-三羥基戊二烯的多酚類化合物，廣泛存在于花生、鳳梨、朝槐、決明、桑子、大黃、首烏、金雀根、葡萄、虎杖、藜蘆等植物中，其中虎杖含量最高，目前臨床已廣泛用于心血管疾病的治療[6]。

2 與SIRT1相關(guān)的PD發(fā)病機(jī)制

研究證實(shí)錯(cuò)誤折疊和聚集蛋白α-突觸核蛋白的累積、神經(jīng)毒素或某些變異蛋白[富亮氨酸重復(fù)激酶2(leucine-rich repeatkinase 2, LRRK2)]導(dǎo)致的線粒體功能障礙與PD發(fā)病相關(guān)[10],其中異常蛋白通過SIRT1-AMPK相關(guān)的自噬作用清除，若自噬作用減弱，其累積可導(dǎo)致PD[11-12]。PD的另一重要發(fā)病機(jī)制為氧化應(yīng)激[13]。PGC-1α是一種增強(qiáng)抗氧化應(yīng)激作用的關(guān)鍵轉(zhuǎn)錄調(diào)節(jié)因子，主要調(diào)節(jié)線粒體代謝及氧化應(yīng)激。相關(guān)實(shí)驗(yàn)通過基因工程使PGC-1α在小鼠神經(jīng)元中過度表達(dá)，同時(shí)用神經(jīng)毒素1-甲基-4-苯基-1,2,3,6-四氫吡啶(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP)誘發(fā)細(xì)胞退化，建立亞急性PD小鼠模型，以黑質(zhì)細(xì)胞中線粒體抗氧化劑超氧化物歧化酶2(superoxide dismutase 2, SOD2)和線粒體型硫氧還蛋白(Trx2)的表達(dá)水平作為神經(jīng)元生存能力指標(biāo)，證明PGC-1α過度表達(dá)使神經(jīng)元免于MPTP誘發(fā)的多巴胺丟失[14]，推測PGC-1α相關(guān)氧化應(yīng)激機(jī)制與PD發(fā)病密切相關(guān)。

3 SIRT1在PD中的保護(hù)機(jī)制

3.1SIRT1/AMPK通路 AMPK是一種極其重要的能量代謝調(diào)節(jié)因子，稱為細(xì)胞的“代謝傳感蛋白”或“能量監(jiān)測器”，其活性主要受AMP/ATP比值調(diào)節(jié)，通過調(diào)控蛋白降解和細(xì)胞自噬作用等穩(wěn)態(tài)進(jìn)而調(diào)節(jié)體內(nèi)的能量代謝，維持細(xì)胞能量平衡[15-16]。有研究顯示熱量限制時(shí)，細(xì)胞內(nèi)NAD+依賴的去乙?；窼IRT1水平升高，通過調(diào)節(jié)轉(zhuǎn)錄而限制能量代謝，延長生物體衰老，推測SIRT1參與了細(xì)胞的能量代謝穩(wěn)態(tài)調(diào)節(jié)[17-18]。提示AMPK與SIRT1在調(diào)節(jié)細(xì)胞內(nèi)能量代謝穩(wěn)態(tài)中存在內(nèi)在聯(lián)系[19]。有實(shí)驗(yàn)顯示，白藜蘆醇可改善魚藤酮誘導(dǎo)的DA神經(jīng)元線粒體損傷，抑制細(xì)胞凋亡，且在SIRT1敲除后，白藜蘆醇可激活A(yù)MPK，但改善線粒體功能的作用消失，證實(shí)白藜蘆醇改善DA神經(jīng)元線粒體損傷主要通過激活A(yù)MPK，進(jìn)而激活SIRT1發(fā)揮相應(yīng)作用[20-21]，說明SIRT1與AMPK之間存在相互調(diào)控的關(guān)系。

有研究顯示，在MPTP建立的亞急性PD小鼠模型中，白藜蘆醇處理后SIRT1和p-AMPK水平明顯升高，而與細(xì)胞凋亡相關(guān)的蛋白Cleaved-caspase 3水平明顯下降，同時(shí)小鼠腦黑質(zhì)區(qū)酪氨酸羥化酶(tyrosine hydroxylase, TH)表達(dá)陽性的神經(jīng)元丟失率降低，紋狀體中TH的表達(dá)量上升；反之，經(jīng)SIRT1特異性抑制劑EX527處理的小鼠，p-AMPK水平明顯下降，而Cleaved-caspase 3蛋白水平明顯升高，且小鼠腦黑質(zhì)區(qū)TH表達(dá)陽性的神經(jīng)元丟失率上升，紋狀體組織中TH的表達(dá)量下降[22]，證實(shí)白藜蘆醇通過激活SIRT1，進(jìn)而激活A(yù)MPK，從而發(fā)揮保護(hù)作用。提示SIRT1通過SIRT1/AMPK通路參與PD進(jìn)程，可作為PD治療的靶點(diǎn)，且白藜蘆醇對PD治療有效。

3.2SIRT1/PGC-1α通路 相對于腦組織較高的氧代謝率，其抗氧化保護(hù)機(jī)制相對缺乏。研究表明，在PD早期氧自由基增多，尚可通過機(jī)體代償反應(yīng)加強(qiáng)紋狀體抗氧化酶系統(tǒng)活性從而抵抗氧自由基損傷，隨著疾病的不斷進(jìn)展，自由基的產(chǎn)生不斷加快，機(jī)體的代償反應(yīng)逐漸降低，進(jìn)而不能抵抗氧自由基產(chǎn)生的損傷，紋狀體內(nèi)氧化和抗氧化應(yīng)激系統(tǒng)逐漸失衡，導(dǎo)致神經(jīng)元損傷、凋亡[23-24]。

PGC-1α是一種多功能蛋白質(zhì)，可激活多細(xì)胞核受體，參與眾多轉(zhuǎn)錄因子的激活，是抗氧化應(yīng)激系統(tǒng)中至關(guān)重要的轉(zhuǎn)錄調(diào)節(jié)因子[24-25]。研究顯示，氧化劑過氧化氫可使抗氧化酶基因、SOD1、SOD2、谷胱甘肽過氧化物酶1及PGC-1α的表達(dá)明顯升高[26]。有實(shí)驗(yàn)證實(shí)，PGC-1α通過增加抗氧化酶活性和表達(dá)水平從而減少細(xì)胞凋亡，而PGC-1α敲除的小鼠過氧化氫酶、SOD1和SOD2的表達(dá)水平與正常小鼠比較顯著降低[27]。推測氧化應(yīng)激可激活PGC-1α，進(jìn)而提高抗氧化酶活性及表達(dá)水平，增強(qiáng)組織的抗氧化能力。

組蛋白乙酰基轉(zhuǎn)移酶復(fù)合體可直接乙?；疨GC-1α的多個(gè)賴氨酸殘基，降低PGC-1α水平且抑制其轉(zhuǎn)錄活性，從而抑制抗氧化作用[28]。反之，SIRT1的活化可維持PGC-1α的去乙?；癄顟B(tài)以保持PGC-1α水平，從而增強(qiáng)抗氧化作用[29]。有學(xué)者發(fā)現(xiàn)過氧化氫可誘導(dǎo)PGC-1α過表達(dá)，還可誘導(dǎo)PGC-1α和SIRT1在細(xì)胞核共聚集，且過氧化氫處理后細(xì)胞的存活率與PGC-1α呈劑量依賴性關(guān)系[30]。有研究顯示，SIRT1抑制劑煙酰胺處理后野生型細(xì)胞抗氧化應(yīng)激能力減弱，而PGC-1α過表達(dá)的細(xì)胞抗氧化應(yīng)激能力則不受影響，證實(shí)PGC-1α位于SIRT1下游。有實(shí)驗(yàn)證明，SIRT1去乙?；疨GC-1α后阻止了蛋白酶體對PGC-1α的降解，致靶基因持續(xù)激活。由此可見，在抗氧化應(yīng)激中SIRT1對PGC-1α發(fā)揮調(diào)節(jié)作用，SIRT1調(diào)節(jié)氧化應(yīng)激條件下PGC-1α的起始和持續(xù)反應(yīng)，在氧化應(yīng)激時(shí)SIRT1上調(diào)和維持PGC-1α水平進(jìn)而發(fā)揮抗氧化應(yīng)激作用[30]。提示SIRT1/PGC-1α通過維持PGC-1α水平進(jìn)而發(fā)揮抗氧化作用，可能在預(yù)防和治療PD中發(fā)揮積極作用。

3.3調(diào)節(jié)炎癥反應(yīng) 有研究證實(shí)，小膠質(zhì)細(xì)胞受刺激后可從具有DA神經(jīng)元保護(hù)作用的靜息狀態(tài)轉(zhuǎn)變?yōu)椴±淼幕罨癄顟B(tài)[31]。相關(guān)文獻(xiàn)顯示，小膠質(zhì)細(xì)胞活化可通過增強(qiáng)氧化應(yīng)激和促進(jìn)促炎癥細(xì)胞因子的產(chǎn)生以影響DA神經(jīng)元[32-34]。有學(xué)者認(rèn)為，神經(jīng)炎癥損害PD患者腦黑質(zhì)DA神經(jīng)元，促使其凋亡[35]。部分學(xué)者表示神經(jīng)炎癥對中樞神經(jīng)系統(tǒng)具有保護(hù)作用[17]。神經(jīng)炎癥究竟是DA神經(jīng)元死亡的主要原因還是神經(jīng)元凋亡后繼發(fā)反應(yīng)目前尚無統(tǒng)一認(rèn)識(shí)，但神經(jīng)炎癥參與PD進(jìn)程是毋庸置疑的[36]。然而，SIRT1通過對NF-κB的脫乙?；饔媒档推滢D(zhuǎn)錄活性，抑制iNOS表達(dá)，降低TNF-α和IL-6水平，抑制神經(jīng)炎癥已得到證實(shí)[37]，由此可見SIRT1可能通過神經(jīng)炎癥參與PD進(jìn)程。

4 展望

綜上，已證實(shí)的與PD相關(guān)的三種作用機(jī)制，即SIRT1-AMPK自噬作用減弱、氧化應(yīng)激和神經(jīng)炎癥均與SIRT1密切相關(guān)，通過SIRT1/AMPK和SIRT1/PGC-1α信號通路調(diào)節(jié)能量代謝、自噬作用、氧化應(yīng)激及保護(hù)線粒體功能等多種途徑減緩或預(yù)防PD進(jìn)程，且SIRT1相關(guān)制劑如白藜蘆醇已用于心血管疾病的治療[6]，提示臨床可將SIRT1相關(guān)研究成果應(yīng)用于PD治療，早日做出重要突破，改善預(yù)后。

[1] Chahine L M, Amara A W, Videnovic A. A systematic review of the literature on disorders of sleep and wakefulness in Parkinson's disease from 2005 to 2015[J].Sleep Med Rev, 2016,2016:1-18.

[2] Maloney E M, Djamshidian A, O'Sullivan S S. Phenomenology and epidemiology of impulsive-compulsive behaviours in Parkinson's disease, atypical Parkinsonian disorders and non-Parkinsonian populations[J].J Neurol Sci, 2017,374:47-52.

[3] Kowal S L, Dall T M, Chakrabarti R,etal. The current and projected economic burden of Parkinson's disease in the United States[J].Mov Disord, 2013,28(3):311-318.

[4] Lee A, Gilbert R M. Epidemiology of Parkinson Disease[J].Neurol Clin, 2016,34(4):955-965.

[5] Gao J, Zhou R, You X,etal. Salidroside suppresses inflammation in a D-galactose-induced rat model of Alzheimer's disease via SIRT1/NF-κB pathway[J].Metab Brain Dis, 2016,31(4):771-778.

[6] Cho S, Namkoong K, Shin M,etal. Cardiovascular Protective Effects and Clinical Applications of Resveratrol[J].J Med Food, 2017,20(4):323-334.

[7] Kupis W, Palyga J, Tomal E,etal. The role of sirtuins in cellular homeostasis[J].J Physiol Biochem, 2016,72(3):371-380.

[8] Ye Q, Ye L, Xu X,etal. Epigallocatechin-3-gallate suppresses 1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12 cells via the SIRT1/PGC-1α signaling pathway[J].BMC Complement Altern Med, 2012,12:82.

[9] Kou X, Li J, Liu X,etal. Ampelopsin attenuates the atrophy of skeletal muscle from d-gal-induced aging rats through activating AMPK/SIRT1/PGC-1α signaling cascade[J].Biomed Pharmacother, 2017,90:311-320.

[10] Moraitou M, Dermentzaki G, Dimitriou E,etal. α-Synuclein dimerization in erythrocytes of Gaucher disease patients: correlation with lipid abnormalities and oxidative stress[J].Neurosci Lett, 2016,613:1-5.

[11] Sun A Y, Wang Q, Simonyi A,etal. Resveratrol as a therapeutic agent for neurodegenerative diseases[J].Mol Neurobiol, 2010,41(2-3):375-383.

[12] Gonzalez-Horta A. The Interaction of Alpha-synuclein with Membranes and its Implication in Parkinson's Disease: A Literature Review[J].Nat Prod Commun, 2015,10(10):1775-1778.

[13] Niranjan R. The role of inflammatory and oxidative stress mechanisms in the pathogenesis of Parkinson's disease: focus on astrocytes[J].Mol Neurobiol, 2014,49(1):28-38.

[14] Wu Y, Li X, Zhu J X,etal. Resveratrol-activated AMPK/SIRT1/autophagy in cellular models of Parkinson's disease[J].Neurosignals, 2011,19(3):163-174.

[15] Li S J, Liu C H, Chang C W,etal. Development of a dietary-induced metabolic syndrome model using miniature pigs involvement of AMPK and SIRT1[J].Eur J Clin Invest, 2015,45(1):70-80.

[16] Yuan Y, Shi M, Li L,etal. Mesenchymal stem cell-conditioned media ameliorate diabetic endothelial dysfunction by improving mitochondrial bioenergetics via the Sirt1/AMPK/PGC-1α pathway[J].Clin Sci (Lond), 2016,130(23):2181-2198.

[17] Wee Yong V. Inflammation in neurological disorders: a help or a hindrance[J].Neuroscientist, 2010,16(4):408-420.

[18] Zhao H, Chen S, Gao K,etal. Resveratrol protects against spinal cord injury by activating autophagy and inhibiting apoptosis mediated by the SIRT1/AMPK signaling pathway[J].Neuroscience, 2017,348:241-251.

[19] Ferretta A, Gaballo A, Tanzarella P,etal. Effect of resveratrol on mitochondrial function: implications in parkin-associated familiar Parkinson's disease[J].Biochim Biophys Acta, 2014,1842(7):902-915.

[20] Price N L, Gomes A P, Ling A J,etal. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function[J].Cell Metab, 2012,15(5):675-690.

[21] Subramaniam S R, Chesselet M F. Mitochondrial dysfunction and oxidative stress in Parkinson's disease[J].Prog Neurobiol, 2013,106-107:17-32.

[22] 郭彥杰,董素艷,趙文娟,等.白藜蘆醇通過SIRT1/AMPK信號通路減輕MPTP誘導(dǎo)的小鼠多巴胺能神經(jīng)元丟失[J].國際神經(jīng)病學(xué)神經(jīng)外科學(xué)雜志,2016,43(2):97-102.

[23] Zhang Y, Dawson V L, Dawson T M. Oxidative stress and genetics in the pathogenesis of Parkinson's disease[J].Neurobiol Dis, 2000,7(4):240-250.

[24] Tsai K L, Cheng Y Y, Leu H B,etal. Investigating the role of Sirt1-modulated oxidative stress in relation to benign paroxysmal positional vertigo and Parkinson's disease[J].Neurobiol Aging, 2015,36(9):2607-2616.

[25] 閆春雷,黃欣,蘇樂群.PGC-1α的轉(zhuǎn)錄調(diào)節(jié)和翻譯后修飾[J].中國生物化學(xué)與分子生物學(xué)報(bào),2015,31(1):12-19.

[26] St-Pierre J, Drori S, Uldry M,etal. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators[J].Cell, 2006,127(2):397-408.

[27] Uldry M, Yang W, St-Pierre J,etal. Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation[J].Cell Metab, 2006,3(5):333-341.

[28] Lerin C, Rodgers J T, Kalume D E,etal. GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1alpha[J].Cell Metab, 2006,3(6):429-438.

[29] Gerhart-Hines Z, Rodgers J T, Bare O,etal. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha[J].EMBO J, 2007,26(7):1913-1923.

[30] Anderson R M, Barger J L, Edwards M G,etal. Dynamic regulation of PGC-1alpha localization and turnover implicates mitochondrial adaptation in calorie restriction and the stress response[J].Aging Cell, 2008,7(1):101-111.

[31] Li J Y, Ma S S, Huang Q Y,etal. The Function of Neuroinflammation in Parkinson Disease[J].Sheng Li Ke Xue Jin Zhan, 2015,46(3):175-179.

[32] Chung Y C, Ko H W, Bok E,etal. The role of neuroinflammation on the pathogenesis of Parkinson's disease[J].BMB Rep, 2010,43(4):225-232.

[33] Lee J K, Tran T, Tansey M G. Neuroinflammation in Parkinson's disease[J].J Neuroimmune Pharmacol, 2009,4(4):419-429.

[34] Wang Q, Liu Y, Zhou J. Neuroinflammation in Parkinson's disease and its potential as therapeutic target[J].Transl Neurodegener, 2015,4:19.

[35] Holmes S, Singh M, Su C, et al. Effects of Oxidative Stress and Testosterone on Pro-Inflammatory Signaling in a Female Rat Dopaminergic Neuronal Cell Line[J].Endocrinology, 2016, 157(7):2824-2835.

[36] Leszek J, Barreto G E, Gasiorowski K,etal. Inflammatory Mechanisms and Oxidative Stress as Key Factors Responsible for Progression of Neurodegeneration: Role of Brain Innate Immune System[J].CNS Neurol Disord Drug Targets, 2016,15(3):329-336.

[37] Ye J, Liu Z, Wei J,etal. Protective effect of SIRT1 on toxicity of microglial-derived factors induced by LPS to PC12 cells via the p53-caspase-3-dependent apoptotic pathway[J].Neurosci Lett, 2013,553:72-77.

R742.5

A

1002-3429(2017)09-0110-04

10.3969/j.issn.1002-3429.2017.09.038

2017-05-09 修回時(shí)間：2017-06-16)

710032 西安，第四軍醫(yī)大學(xué)西京醫(yī)院急診科