吳安平，慶宏，全貞貞

Rab蛋白家族在神經(jīng)類疾病中的作用

吳安平，慶宏，全貞貞

北京理工大學(xué)生命學(xué)院分子醫(yī)學(xué)和生物診療工信部重點(diǎn)實(shí)驗(yàn)室，北京 100081

細(xì)胞內(nèi)膜囊泡運(yùn)輸是一個(gè)復(fù)雜的通路網(wǎng)絡(luò)，Rab GTPases是膜囊泡運(yùn)輸?shù)闹饕{(diào)節(jié)劑，通常被認(rèn)為是細(xì)胞內(nèi)吞和分泌系統(tǒng)中各種細(xì)胞器和囊泡的特異性標(biāo)記和識(shí)別物。與Rab蛋白相關(guān)的軸突運(yùn)輸、內(nèi)體運(yùn)輸發(fā)生障礙是造成神經(jīng)退行性疾病的重要原因之一。本文主要介紹了Rab蛋白在多種神經(jīng)退行性疾病病理機(jī)制中的作用機(jī)理與調(diào)控機(jī)制，同時(shí)討論了線粒體和膠質(zhì)細(xì)胞功能異常與Rab蛋白之間的關(guān)聯(lián)。深入探究Rab蛋白的作用機(jī)制對(duì)人類神經(jīng)性疾病的早期診斷和治療具有潛在的指導(dǎo)意義。

Rab蛋白；神經(jīng)退行性疾?。荒つ遗葸\(yùn)輸；線粒體；星型膠質(zhì)細(xì)胞

中國是世界上癡呆癥患者最多的國家，給公共和衛(wèi)生保健系統(tǒng)帶來了沉重負(fù)擔(dān)。研究表明，2016年我國老年人口患癡呆癥的概率是5.6%[1]，目前我國的癡呆癥患者大約有3100萬，給患者及其家人帶來沉重負(fù)擔(dān)，將會(huì)引發(fā)越來越嚴(yán)重的公共衛(wèi)生問題和社會(huì)問題[2]。

癡呆等認(rèn)知障礙的形成是由于神經(jīng)元結(jié)構(gòu)和功能逐漸喪失，以及神經(jīng)元死亡和膠質(zhì)細(xì)胞失衡所導(dǎo)致的，主要包括阿爾茲海默病(Alzheimer’s disease, AD)、帕金森病(Parkinson’s disease, PD)、亨廷頓病(Huntington’s disease, HD)、肌萎縮性側(cè)索硬化癥(amyotrophic lateral sclerosis, ALS)、不同類型脊髓小腦共濟(jì)失調(diào)病等神經(jīng)類疾病。研究表明Rab蛋白能夠調(diào)節(jié)神經(jīng)元細(xì)胞的內(nèi)吞和軸突運(yùn)輸，參與多種神經(jīng)類疾病的病理進(jìn)程。本文就Rab蛋白如何調(diào)控各類神經(jīng)類疾病進(jìn)行了歸納和分析，進(jìn)一步闡述了Rab蛋白在的作用機(jī)制，為今后探究Rab蛋白在神經(jīng)類疾病中的作用提供了思路和參考。

1 Rab蛋白結(jié)構(gòu)

Rab蛋白是存在于細(xì)胞質(zhì)膜和細(xì)胞器膜中的一類調(diào)節(jié)型小分子GTP結(jié)合蛋白，是Ras超家族中最大的亞家族。Rab蛋白在進(jìn)化上高度保守，幾乎存在于所有的真核生物中。Rab蛋白平均分子量大小為25 kDa，約由200個(gè)氨基酸組成。Rab蛋白含G結(jié)構(gòu)域、N端與C端，其中，G結(jié)構(gòu)域高度保守，N端與C端高度可變[3]。G結(jié)構(gòu)域包含6個(gè)β折疊、5個(gè)α螺旋及5個(gè)多肽環(huán)，多肽環(huán)的氨基酸序列高度保守，是Mg2+和鳥嘌呤的結(jié)合位點(diǎn)，同時(shí)催化GTP水解。Rab蛋白的羧基末端包含-XXXCC-、-XXCCX-、-XCCXX-、-CCXXX-或-XXCXC-基本序列，其中兩個(gè)半胱氨酸是異戊二烯化的底物。這種修飾對(duì)于膜結(jié)合至關(guān)重要。羧基末端高變區(qū)是必需的，但不足以將Rab蛋白正確靶向到細(xì)胞中的特定位置[3]。大多數(shù)Rab蛋白通過翻譯后在羧基端附近的兩個(gè)半胱氨酸上將兩個(gè)香葉基(20碳聚異戊二烯基)基團(tuán)與膜或膜蛋白復(fù)合物緊密結(jié)合，少數(shù)Rab蛋白只有一個(gè)香葉基[4]。N端的作用可能是參與指導(dǎo)C端半胱氨酸進(jìn)行異戊二烯化修飾。G結(jié)構(gòu)域的“開關(guān)”區(qū)域(稱為開關(guān)1和2)通過與GTP結(jié)合產(chǎn)生穩(wěn)定的構(gòu)象，是Rab蛋白特異性識(shí)別其細(xì)胞效應(yīng)子關(guān)鍵區(qū)域。不同的Rab蛋白在進(jìn)行開“ON”和關(guān)“OFF”狀態(tài)切換時(shí)，可能會(huì)發(fā)生比較靈活的構(gòu)象變化[5]。對(duì)Rab蛋白突變體及嵌合體的研究表明，分子開關(guān)I和分子開關(guān)II、高度可變的N端和C端是Rab蛋白重要功能的決定因素。

Rab蛋白的主要功能是調(diào)節(jié)細(xì)胞信號(hào)的傳導(dǎo)、細(xì)胞的生長和分化[6]。Rab GTPases作為分子開關(guān)，在GTP結(jié)合的活性形式和GDP結(jié)合的非活性形式之間轉(zhuǎn)換，控制細(xì)胞內(nèi)囊泡運(yùn)輸?shù)母鱾€(gè)方面。Rab-GTP結(jié)合型和Rab-GDP結(jié)合型之間的循環(huán)受蛋白質(zhì)調(diào)節(jié)劑嚴(yán)格控制：GDP解離抑制劑(GDP disso-ciation inhibitors, GDI)調(diào)控Rab蛋白與膜的連接及Rab蛋白從膜上解離，GDI作為循環(huán)因子起作用，只與異戊二烯化修飾的無活性的Rab蛋白結(jié)合，將Rab-GDP保持在胞液中。伴隨著Rab蛋白與供體囊泡的膜或膜蛋白復(fù)合物結(jié)合，鳥嘌呤交換因子(guanine nucleotide exchange factor, GEF)催化Rab- GDP形式轉(zhuǎn)化成Rab-GTP形式，Rab蛋白被激活，Rab-GTP與下游效應(yīng)子相互作用，使效應(yīng)子功能發(fā)生變化；GTPase活化蛋白(GTPase accelerating protein, GAP)催化GTP水解，Rab蛋白失活，不再與效應(yīng)子相互作用；GDI從膜上抽出Rab-GDP，與其形成復(fù)合物，又循環(huán)到胞液中。通過激活/失活循環(huán)，Rab蛋白作為分子開關(guān)將上游信號(hào)傳遞給下游效應(yīng)子(圖1)。Rab蛋白在其活性形式時(shí)與許多不同的蛋白質(zhì)相互作用，這些蛋白質(zhì)被稱為Rab蛋白的效應(yīng)子。Rab蛋白的效應(yīng)子在囊泡的形成、囊泡沿細(xì)胞骨架的轉(zhuǎn)運(yùn)及囊泡與靶膜的拴系錨定等階段中發(fā)揮作用[7]。

2 Rab蛋白在細(xì)胞中的調(diào)控途徑

Rab蛋白最主要的功能是調(diào)控細(xì)胞內(nèi)吞，內(nèi)吞運(yùn)輸系統(tǒng)主要由內(nèi)吞、循環(huán)、降解等子系統(tǒng)組成。其中，內(nèi)吞循環(huán)運(yùn)輸負(fù)責(zé)將膜上大分子送回質(zhì)膜回收再利用，在細(xì)胞極性形成和維持、細(xì)胞分裂及遷移、神經(jīng)突觸可塑性、免疫應(yīng)答、生長因子受體調(diào)控等過程中不可或缺[8]。降解途徑導(dǎo)向晚期內(nèi)含體和溶酶體，貨物在其中發(fā)生降解[9]。沿內(nèi)吞途徑的每個(gè)運(yùn)輸步驟均由不同的Rab蛋白介導(dǎo)：Rab5介導(dǎo)貨物從質(zhì)膜到早期內(nèi)含體的運(yùn)輸并充當(dāng)早期內(nèi)含體的標(biāo)記物[10]；而Rab7則調(diào)節(jié)貨物從早期到晚期內(nèi)含體的運(yùn)輸并充當(dāng)晚期內(nèi)含體的標(biāo)記物[11]；Rab4，Rab11和Rab35介導(dǎo)回收途徑；Rab4和Rab35調(diào)控貨物從早期內(nèi)含體、循環(huán)內(nèi)含體直接返回質(zhì)膜的快速回收[12,13]；Rab11控制循環(huán)內(nèi)含體的回收[14](圖2)。研究表明，晚期內(nèi)含體和溶酶體功能異常，在細(xì)胞衰老和神經(jīng)退行性疾病(如帕金森病和阿爾茨海默病)中起著關(guān)鍵作用。

圖1 Rab蛋白的功能循環(huán)示意圖

Rab蛋白與GDI、GDP結(jié)合保存在胞液中，由GEF激活轉(zhuǎn)移到供體膜上轉(zhuǎn)化成Rab-GTP形式，使下游效應(yīng)子發(fā)揮作用，激活態(tài)的Rab-GTP蛋白被GAP催化水解，隨后GDI與Rab-GDP又形成復(fù)合物，循環(huán)到胞液中，形成循環(huán)。

圖2 Rab蛋白在細(xì)胞中的分布

ER：內(nèi)質(zhì)網(wǎng)；TGN: 反高爾基網(wǎng)絡(luò)；EE：早期內(nèi)含體；LE：晚期內(nèi)含體；RE：循環(huán)內(nèi)含體；AP：自噬體；ERGIC：內(nèi)質(zhì)網(wǎng)一高爾基體中介組分；L/V：溶酶體/液泡；PAS：前自噬體；SV：分泌囊泡/顆粒。

3 Rab蛋白在神經(jīng)元中的相關(guān)功能

神經(jīng)元的特殊形態(tài)和功能高度依賴于膜運(yùn)輸?shù)膰?yán)格調(diào)節(jié)。內(nèi)吞功能障礙破壞了雙向軸突運(yùn)輸和突觸小泡與靶膜的對(duì)接，從而導(dǎo)致神經(jīng)運(yùn)輸和神經(jīng)營養(yǎng)信號(hào)發(fā)生異常。軸突運(yùn)輸?shù)母淖?，特別是神經(jīng)營養(yǎng)蛋白受體在軸突運(yùn)輸?shù)母淖兣c幾種人類神經(jīng)退行性疾病都有關(guān)聯(lián)[15,16]。Rab3A是突觸活性區(qū)的結(jié)構(gòu)成分，與其他核心活性區(qū)蛋白R(shí)IM1和MUNC13一起形成三元復(fù)合物，調(diào)節(jié)突觸小泡與膜的結(jié)合過程，以釋放神經(jīng)遞質(zhì)[17]。Rab3蛋白還參與淀粉樣前體蛋白(amyloid protein precursor, APP)的快速軸突運(yùn)輸[18]。Rab7控制神經(jīng)營養(yǎng)蛋白受體的逆行軸突運(yùn)輸[19]，Rab7損傷可誘導(dǎo)神經(jīng)營養(yǎng)因子TrkA在內(nèi)含體中的積累，進(jìn)而阻滯神經(jīng)營養(yǎng)蛋白逆行轉(zhuǎn)運(yùn)[20]。Rab26位于突觸小泡表面，自噬蛋白Atg16L1、LC3和Rab33B被募集到這些突觸小泡中，從而連接了突觸小泡與自噬機(jī)制[21]。與其他細(xì)胞類型相比，神經(jīng)元可能對(duì)蛋白質(zhì)水平的輕微升高或降低更敏感，特定蛋白質(zhì)水平的微小變化也可能導(dǎo)致神經(jīng)元功能障礙和死亡。

4 Rab蛋白在神經(jīng)退行性疾病中的作用

4.1 阿爾茨海默病

阿爾茨海默病是神經(jīng)變性和癡呆癥的最常見形式。超過90%~95%的AD病例是散發(fā)性(sporadic AD，SAD)且與已知的疾病突變無關(guān)。大約5%~10%的病例被歸類為家族性AD (familial AD, FAD)，與早老素1、早老素2和APP的突變有關(guān)。這些突變導(dǎo)致β-淀粉樣蛋白(β-amyloid, Aβ)的產(chǎn)生發(fā)生異常。在Aβ形成途徑中，APP首先被β-分泌酶切割，其中主要發(fā)揮作用的是β-分泌酶1 (β-site APP cleaving enzyme 1, BACE1)，使APP 596~597位氨基酸之間發(fā)生裂解，釋放一個(gè)可溶性的約100 kDa的N端片段sAPPβ，在膜上留下一個(gè)12 kDa的C端片段C99，C99片段被γ-分泌酶切割，從而產(chǎn)生Aβ。AD患者中Aβ產(chǎn)生過量，作為細(xì)胞外沉積物積聚在腦中，是形成老年斑的主要成分，其與由tau蛋白異常磷酸化導(dǎo)致的神經(jīng)原纖維纏結(jié)是AD最主要的兩大病理特征[22]。

Rab11b位于早期和晚期內(nèi)體，高爾基復(fù)合體和內(nèi)質(zhì)網(wǎng)中。通常與再循環(huán)內(nèi)含體有關(guān)，調(diào)控著反面高爾基體管網(wǎng)狀結(jié)構(gòu)與內(nèi)吞、在循環(huán)內(nèi)含體或質(zhì)膜之間的物質(zhì)運(yùn)輸。通過共聚焦分析和免疫熒光染色顯示，在Rab11B陽性循環(huán)內(nèi)含體中觀察到BACE1沿樹突和軸突定位并運(yùn)輸。沉默導(dǎo)致內(nèi)在的BACE1在體細(xì)胞中積累，伴隨著軸突中BACE1的水平降低[23]。這些結(jié)果表明，Rab11是神經(jīng)元中BACE1的分選調(diào)節(jié)劑，對(duì)于BACE1的軸突分選至關(guān)重要。另外，siRNA敲低的表達(dá)顯著降低了sAPPβ和Aβ的水平，這提示Rab11功能障礙可能是部分散發(fā)性阿爾茨海默病病例的發(fā)病機(jī)制之一[24]。Rab21在蛋白從早期內(nèi)含體向晚期內(nèi)含體轉(zhuǎn)運(yùn)過程中發(fā)揮作用，研究發(fā)現(xiàn)過表達(dá)可以通過促進(jìn)γ-分泌酶的內(nèi)吞及向晚期內(nèi)含體的遷移來影響其活性，進(jìn)而促進(jìn)Aβ的產(chǎn)生[25]。沉默會(huì)降低Aβ水平，而不影響sAPPβ。這意味著這些Rab GTPases會(huì)影響γ-分泌酶對(duì)APP的水解或Aβ的運(yùn)輸[25,26]。同濟(jì)大學(xué)生命科學(xué)與技術(shù)學(xué)院的裴剛院士課題組通過采用雙分子熒光互補(bǔ)技術(shù)結(jié)合熒光共振能量轉(zhuǎn)移技術(shù)發(fā)現(xiàn)ADAM10/BACE1二元復(fù)合物主要位于早期內(nèi)含體，進(jìn)一步觀察到γ-分泌酶與α-/β-分泌酶二元復(fù)合物相互作用，表明α-、β-和γ-分泌酶可能形成三元復(fù)合物[27]，這提示影響γ-分泌酶的Rab21蛋白可能同時(shí)調(diào)控α-分泌酶和β-分泌酶。Rab8A/Rab8是極化運(yùn)輸?shù)闹匾{(diào)節(jié)劑，并參與反高爾基網(wǎng)絡(luò)至基底外側(cè)質(zhì)膜的運(yùn)輸，突起形成和纖毛發(fā)生[28,29]。與對(duì)照相比，來自AD腦組織質(zhì)膜部分的Rab8水平顯著增加[30]。另有研究發(fā)現(xiàn)，沉默也可增加tau蛋白分泌。Rab1A與高爾基體膜相關(guān)，沉默會(huì)誘導(dǎo)高爾基體碎裂，這表明Rab介導(dǎo)的高爾基體動(dòng)力學(xué)可能參與調(diào)節(jié)tau蛋白分泌[31]。Rab3蛋白參與調(diào)控APP在軸突的快速運(yùn)輸。沉默和能夠降低總體APP蛋白水平，這表明Rab3在APP的運(yùn)輸和維持中發(fā)揮了作用[26]。

Ras and Rab Interactor 3 (RIN3)是Rab5 GTPase家族的鳥嘌呤核苷酸交換因子(GEF)，美國加州大學(xué)圣地亞哥分校醫(yī)學(xué)院的吳承標(biāo)課題組發(fā)現(xiàn)，在AD發(fā)病早期，的mRNA水平在皮質(zhì)和海馬中均顯著增加，這一現(xiàn)象先于β-淀粉樣蛋白沉積產(chǎn)生[32]。在APP/PS1小鼠的基底前腦膽堿能神經(jīng)元中選擇性上調(diào)。由于RIN3是Rab5的GEF，因此增加的表達(dá)可能有助于APP/PS1小鼠基底前腦膽堿能神經(jīng)元中Rab5早期內(nèi)含體的增大。通過質(zhì)譜分析發(fā)現(xiàn)，RIN3向Rab5早期內(nèi)含體募集了另外兩個(gè)AD危險(xiǎn)因素BIN1和CD2AP，進(jìn)而損害APP的運(yùn)輸和加工，導(dǎo)致具有神經(jīng)元毒性的APP-CTF的產(chǎn)生增加。RIN3/BIN1復(fù)合物的增加還可以促進(jìn)Tau蛋白過度磷酸化。Rab5在內(nèi)含體運(yùn)輸、突觸和突觸功能中起重要作用[32]。它還參與了興奮性突觸傳遞的長期增強(qiáng)和抑制過程，這對(duì)于學(xué)習(xí)和記憶功能非常重要[33,34]。Rab5的激活可能會(huì)削弱突觸功能和細(xì)胞之間的通信，導(dǎo)致信號(hào)傳遞到內(nèi)含體的軸突運(yùn)輸減少和神經(jīng)元萎縮。

在AD模型鼠中觀察到明顯增大的溶酶體聚集在一起，顯示出溶酶體功能障礙。溶酶體呈現(xiàn)較低的pH值時(shí)，Aβ42可能被錯(cuò)誤折疊成穩(wěn)定的聚集體，該聚集體能夠在細(xì)胞內(nèi)繁殖并隨后成核，并在胞外形成淀粉樣斑塊[35]。最近發(fā)現(xiàn)，參與內(nèi)含體，自噬體和溶酶體運(yùn)輸?shù)腞ab7A可以調(diào)節(jié)tau蛋白分泌。抑制的表達(dá)后，tau蛋白在Thr181和Ser422位點(diǎn)的磷酸化完全被消除，Ser202和Ser404處的磷酸化也顯著降低，tau蛋白磷酸化的減少可能有助于其分泌減少。與此一致的是的顯性負(fù)突變和組成型活性形式的過表達(dá)分別減少和增加了tau蛋白分泌[36]。AD患者的人腦和AD小鼠模型腦中可以檢測(cè)到Rab7A水平升高，且 Rab7A和tau蛋白之間存在共定位現(xiàn)象，這進(jìn)一步表明Rab7A可能促進(jìn)tau蛋白在AD中的積累[36]。

4.2 帕金森病

帕金森病也是一種常見的神經(jīng)退行性疾病，其臨床表現(xiàn)為運(yùn)動(dòng)缺陷，包括靜息性震顫和肌肉僵硬[37]。其病理特征主要是在黑質(zhì)致密部中積累了由α-突觸核蛋白(α-synuclein, α-syn)組成的路易小體和多巴胺能神經(jīng)元的選擇性變性。約95%的PD病例為散發(fā)性，其余為家族性。突觸核蛋白和的基因突變是引起家族性和散發(fā)性帕金森病的主要原因。人類遺傳學(xué)的最新進(jìn)展指出，膜運(yùn)輸缺陷是PD致病的關(guān)鍵途徑[38]。α-Syn是神經(jīng)元中高度豐富的蛋白質(zhì)，溶酶體過程的破壞會(huì)影響其代謝[39]。

在PD動(dòng)物模型中已經(jīng)證明，過量的α-syn會(huì)損害Rab蛋白依賴的細(xì)胞內(nèi)運(yùn)輸，研究發(fā)現(xiàn)的過表達(dá)可能逆轉(zhuǎn)細(xì)胞內(nèi)毒性，從而阻止神經(jīng)元的丟失[40]。α-syn的內(nèi)吞與再循環(huán)可能由Rab11A和Rab13介導(dǎo)，同時(shí)Rab11A，Rab13和Rab8B可能也參與α-syn在包涵體中的清除[41]。Dinter等[42]發(fā)現(xiàn)在HEK293細(xì)胞中，的過表達(dá)能夠增加α-syn的清除率，其效應(yīng)子FYCO1需要活性Rab7才能發(fā)揮作用，繼而刺激α-突觸核蛋白的降解。在飛行模型中，Rab7和FYCO1可以挽救突變體α-syn誘導(dǎo)的運(yùn)動(dòng)功能障礙，因此Rab7可以作為治療PD的潛在靶點(diǎn)[42]。

LRRK2位于高爾基體、高爾基相關(guān)囊泡、內(nèi)質(zhì)網(wǎng)、線粒體和溶酶體中，是囊泡運(yùn)輸?shù)囊话阏{(diào)節(jié)器。LRRK2可能通過調(diào)節(jié)與內(nèi)含體分選相關(guān)的Rab GTPases (即Rab29、Rab8A、Rab10)在開關(guān)II區(qū)的保守蘇氨酸殘基處的磷酸化，進(jìn)而調(diào)節(jié)貨物的囊泡運(yùn)輸。反過來，LRRK2激酶的活性主要受高爾基復(fù)合體內(nèi)Rab29和內(nèi)含體中與逆轉(zhuǎn)錄子相關(guān)的VPS35的調(diào)控[43]。磷酸蛋白質(zhì)組學(xué)的結(jié)果表明，包括Rab3A、Rab29、Rab8A、Rab10、Rab12和Rab43在內(nèi)的幾種Rab蛋白均是LRRK2的底物[44~46]。通過LRRK2激酶的體外活性測(cè)定還發(fā)現(xiàn)，Rab GTPase蛋白的一個(gè)子集，包括Rab1A、Rab3C、Rab35可以與LRRK2相互作用并被其磷酸化[47]。

越來越多的證據(jù)表明，沉默內(nèi)源性表達(dá)導(dǎo)致自噬缺陷，從而使α-syn的異常積累，進(jìn)而導(dǎo)致PD的發(fā)生[39]。Rab29在溶酶體應(yīng)激條件下，將LRRK2募集到較大的溶酶體中，易位至異常的溶酶體后，LRRK2募集其底物Rab8和Rab10，并通過介導(dǎo)其功能性下游調(diào)節(jié)子，EH結(jié)構(gòu)域結(jié)合蛋白1 (EHBP1)和EHBP1樣蛋白1 (EHBP1L1)來促進(jìn)溶酶體分泌[48]。鑒于EHBP1和EHBP1L1參與內(nèi)含體和制管膜曲率的形成[49,50]，可以推測(cè)LRRK2-Rab途徑調(diào)節(jié)溶酶體的形態(tài)。

研究證明Rab35是LRRK2的下游效應(yīng)子。Rab GTPases上的磷酸化位點(diǎn)突變會(huì)引起原代皮層神經(jīng)元中的神經(jīng)毒性和多巴胺能神經(jīng)元的變性，這在Rab35磷酸突變體中尤為嚴(yán)重[47]。韓國首爾國立大學(xué)醫(yī)學(xué)院李勝在課題組在α-syn轉(zhuǎn)基因小鼠中發(fā)現(xiàn)，LRRK2激酶的抑制降低了α-syn的病理特征并增強(qiáng)了α-syn向溶酶體的運(yùn)輸[51]?？紤]到Rab35可以通過調(diào)節(jié)多囊泡體向質(zhì)膜的運(yùn)輸和對(duì)接來調(diào)控外泌體的分泌[52]，猜測(cè)LRRK2-RAB35途徑的激活使α-syn避開了溶酶體降解途徑，而是導(dǎo)致其進(jìn)入分泌途徑，從而促進(jìn)了該蛋白的積累[53]。

4.3 肌萎縮性側(cè)索硬化癥

肌萎縮性側(cè)索硬化癥是一種進(jìn)行性神經(jīng)系統(tǒng)變性疾病，主要影響大腦和脊髓中的運(yùn)動(dòng)神經(jīng)元[54]。

與AD和PD相似，所有ALS病例中有90%是散發(fā)型的；有10%來自家族，是由編碼多種蛋白質(zhì)的基因突變引起的，這些基因包括(Rab5的鳥嘌呤核苷酸交換因子)，(染色體9上的開放讀碼框72)，(超氧化物歧化酶1)，(交易反應(yīng)性DNA結(jié)合蛋白43)，(肉瘤融合蛋白)和(VAMP (小突觸泡蛋白)相關(guān)的蛋白B)等[55~57]。

ALS在兒童期發(fā)作是由于基因功能喪失的突變所致，ALS2通過激活Rab5在早期內(nèi)含體中的成熟發(fā)揮關(guān)鍵作用。ALS2和Rab5相互作用可以調(diào)節(jié)神經(jīng)營養(yǎng)蛋白的信號(hào)傳導(dǎo)[58]。

在ALS患者的運(yùn)動(dòng)神經(jīng)元中，C9orf72主要定位于Rab5陽性的早期內(nèi)含體。在神經(jīng)元細(xì)胞系和原代皮層神經(jīng)元中，C9orf72與Rab1、Rab5、Rab7和Rab11共定位[57]。沉默后，TrkB的內(nèi)吞作用被抑制，這表明這些患者的內(nèi)含體運(yùn)輸受到損害[59]。已有報(bào)道顯示C9orf72與Rab蛋白的相互作用能夠調(diào)節(jié)運(yùn)動(dòng)神經(jīng)元中內(nèi)含體的運(yùn)輸，該過程是溶酶體發(fā)生所必需。C9orf72的耗竭會(huì)損害自噬，并導(dǎo)致聚集體的異常聚集，而聚集體是ALS發(fā)病的主要特征。沉默后，LC3II：LC3I比例顯著增加，表明自噬體形成失調(diào)。

Rab1與突變型TDP-43，F(xiàn)US和SOD1廣泛共定位于神經(jīng)元細(xì)胞中，并且Rab1在散發(fā)性ALS患者的脊髓運(yùn)動(dòng)神經(jīng)元中參與形成包涵體。SOD1、TDP-43或FUS的突變會(huì)導(dǎo)致Rab1的定位出現(xiàn)錯(cuò)誤，進(jìn)而導(dǎo)致內(nèi)質(zhì)網(wǎng)–高爾基體網(wǎng)絡(luò)中的蛋白質(zhì)運(yùn)輸受損。而這些缺失可以通過的過表達(dá)來挽救[60]。的過表達(dá)對(duì)mSOD1、mTDP-43和mFUS誘導(dǎo)的內(nèi)質(zhì)網(wǎng)應(yīng)激具有保護(hù)作用[55]。Rab1介導(dǎo)的內(nèi)質(zhì)網(wǎng)–高爾基體運(yùn)輸途徑可能是ALS中的新型治療靶點(diǎn)。

4.4 亨廷頓病

亨廷頓病是一種致命的神經(jīng)退行性疾病，每100,000名居民中有5~10例患病，典型發(fā)病年齡為30~40歲?；颊邥?huì)遭受一系列復(fù)雜的精神、認(rèn)知和運(yùn)動(dòng)障礙，直至死亡。亨廷頓病是由亨廷頓基因()中的聚谷氨酰胺()重復(fù)擴(kuò)增引起的常染色體顯性遺傳病。重復(fù)序列的長度與發(fā)病年齡成正比，但是遺傳變異和環(huán)境因素改變了這種相關(guān)性[61]。它是由三核苷酸CAG在亨廷頓基因()基因5?末端附近的多態(tài)性區(qū)域發(fā)生異常擴(kuò)增引起的。這種顯性突變不僅耗盡了編碼的亨廷頓蛋白，破壞了其生理功能，而且還產(chǎn)生了折疊錯(cuò)誤的蛋白，即突變體Htt，并導(dǎo)致紋狀體中的中棘神經(jīng)元死亡[62]。

Rab8 GTPase調(diào)節(jié)反面高爾基體網(wǎng)管狀結(jié)構(gòu)向質(zhì)膜的運(yùn)輸，optineurin是其效應(yīng)子，二者形成的復(fù)合物在高爾基復(fù)合體到基底外側(cè)質(zhì)膜的極化膜運(yùn)輸過程中以及神經(jīng)元的樹突中起重要作用[63]。的突變與optineurin-Rab8復(fù)合物的相互作用減少，從而導(dǎo)致網(wǎng)格蛋白依賴性高爾基體到溶酶體區(qū)室的運(yùn)輸發(fā)生改變[64]。此外，Htt和HAP40(Htt相關(guān)蛋白40)形成的復(fù)合物是Rab5的效應(yīng)子，可控制早期內(nèi)含體的運(yùn)動(dòng)活性[65]。的過表達(dá)降低了Htt突變蛋白的聚集，而沉默會(huì)抑制內(nèi)吞作用并阻斷自噬，從而增加了polyQ的聚集[66]。Rab11是參與內(nèi)含體再循環(huán)的Rab蛋白，內(nèi)循環(huán)是細(xì)胞維持質(zhì)膜成分的主要途徑。突變體Htt抑制Rab11-GDP到Rab11-GTP的核苷酸交換，從而抑制Rab11的活性并導(dǎo)致細(xì)胞中轉(zhuǎn)鐵蛋白受體的再循環(huán)減慢。HD患者中Rab11活性和內(nèi)體循環(huán)功能的異?？赡芘c除轉(zhuǎn)鐵蛋白外的許多關(guān)鍵蛋白的轉(zhuǎn)運(yùn)有關(guān)，并對(duì)神經(jīng)元的樹突和軸突產(chǎn)生影響[67]。

在HD轉(zhuǎn)基因小鼠中，觀察到靠近Htt聚集體的神經(jīng)元樹突棘較少，提示樹突棘損失可能是Htt聚集體清除率下降的早期結(jié)果。通過在海馬神經(jīng)元中過表達(dá)可消除表達(dá)Htt的原代鼠神經(jīng)元中樹突棘的喪失，這表明突觸功能障礙與Rab11受損可能有早期HD的發(fā)病相關(guān)[68]。

HD與軸突運(yùn)輸?shù)母淖冇嘘P(guān)。在紋狀體神經(jīng)元中，的表達(dá)破壞了軸突的快速運(yùn)輸[69]。在果蠅HD模型中，的過表達(dá)能夠恢復(fù)早期的突觸功能障礙，包括突觸前囊泡大小的減少，數(shù)量振幅的減少和誘發(fā)的突觸傳遞以及幼蟲爬行的改變等[70]。

4.5 夏科特–瑪麗–牙齒2B型

夏科特–瑪麗–牙齒(Charcot–Marie-tooth, CMT)病是最常見的遺傳性神經(jīng)肌肉疾病，該病是由于幾種不同基因的突變導(dǎo)致相似的表型。CMT主要分為1類(CMT1)和2類(CMT2)形式。CMT1是特征為神經(jīng)傳導(dǎo)速度降低的顯性遺傳性脫髓鞘神經(jīng)病，而CMT2是特征為神經(jīng)傳導(dǎo)速度正?；蚵杂薪档偷娘@性遺傳性軸突神經(jīng)病。除了這些主要類別外，CMT中還包括其他稀有形式[71]。在此著重介紹直接與Rab相關(guān)的CMT疾病，即CMT2B型，其表現(xiàn)包括嚴(yán)重的感覺喪失，遠(yuǎn)端肌肉無力以及由于反復(fù)感染引起的足部潰瘍，感染甚至截肢的頻繁發(fā)生。

Rab7中高度保守的氨基酸殘基的5個(gè)錯(cuò)義突變與CMT2B型表型相關(guān)。點(diǎn)突變引起Rab7蛋白水平升高或降低，進(jìn)而影響Rab7控制的神經(jīng)營養(yǎng)蛋白的轉(zhuǎn)運(yùn)和信號(hào)傳導(dǎo)、神經(jīng)突向外生長以及神經(jīng)元遷移[20,72]。由于神經(jīng)營養(yǎng)蛋白受體的內(nèi)吞作用和逆行軸突運(yùn)輸對(duì)于神經(jīng)營養(yǎng)蛋白信號(hào)的傳導(dǎo)和控制神經(jīng)元的分化、可塑性和存活至關(guān)重要，因此神經(jīng)營養(yǎng)蛋白運(yùn)輸障礙可能會(huì)導(dǎo)致嚴(yán)重的神經(jīng)變性[73,74]。

在一名CMT2B患者腓腸神經(jīng)活檢中，發(fā)現(xiàn)Rab7效應(yīng)子-Rab相互作用溶酶體蛋白(Rab interacting lysosomal protein, RILP)被下調(diào)，導(dǎo)致受體降解和信號(hào)衰減。RILP不僅是晚期內(nèi)體/溶酶體的正常分布所必需的，而且是晚期內(nèi)體中腔內(nèi)囊泡的形成所必需的[75,76]。但是，GTP水解不足可能會(huì)導(dǎo)致Rab7突變體隔離RILP，從而降低RILP作用于其他方面(如內(nèi)含體)的能力。由于Rab7是普遍存在的RabGTPase，因此這種罕見疾病也顯示了其神經(jīng)元對(duì)膜運(yùn)輸?shù)淖兓哂忻舾行缘奶攸c(diǎn)。

5 Rab GTPases介導(dǎo)線粒體和星形膠質(zhì)細(xì)胞的功能

Rab GTPas介導(dǎo)的膜運(yùn)輸與神經(jīng)退行性疾病的關(guān)聯(lián)是多種多樣的。在神經(jīng)退行性疾病中，在受損線粒體吞噬過程中Rab蛋白同樣發(fā)揮重要的調(diào)控作用。線粒體的狀態(tài)直接影響神經(jīng)元的發(fā)育、功能和存活。神經(jīng)元是長壽細(xì)胞，在整個(gè)生命周期中都存在，因此更容易受到線粒體功能障礙引起的累積損傷的影響。在AD患者神經(jīng)元內(nèi)的異常溶酶體中，發(fā)現(xiàn)了未消化的受損線粒體[77]。在PD的發(fā)病機(jī)理中LRRK2、α-Syn會(huì)損害線粒體和線粒體功能，因此造成的線粒體受損是必然的。ALS的致病基因涉及線粒體和線粒體調(diào)控基因(如、Ser/Thr蛋白激酶()、和超氧化物歧化酶1 ())[78]。功能障礙線粒體的積累已成為患者和動(dòng)物模型中受累神經(jīng)元的共同特征，可能出現(xiàn)在明顯的認(rèn)知缺陷之前。

Rab7的活性受兩個(gè)Rab7 GAPs (TBC1D15和TBC1D17)的調(diào)控，同時(shí)Rab7也被募集到線粒體外膜，在那里動(dòng)員囊泡以建立自噬體。TBC1D15和TBC1D17的耗盡會(huì)導(dǎo)致Rab7在線粒體上積累，并導(dǎo)致自噬體樣結(jié)構(gòu)異常積累，從而延遲并阻礙受損線粒體的清除[79,80]。這些GAPs在空間上控制Rab7活性，Rab7活性本身控制了囊泡向自噬體膜的募集。處于其GTP結(jié)合活性狀態(tài)的Rab32參與線粒體的分裂[81]。Rab35促進(jìn)自噬受體NDP52的募集以及與泛素的結(jié)合，從而促進(jìn)異種吞噬、線粒體吞噬和自噬體的成熟[82]。

許多研究表明AD、PD和HD等神經(jīng)退行性疾病的發(fā)病機(jī)制中存在星形膠質(zhì)細(xì)胞的功能異常，并伴有Rab蛋白水平的變化。神經(jīng)炎癥是所有神經(jīng)退行性疾病的重要組成部分，其中小膠質(zhì)細(xì)胞和星形膠質(zhì)細(xì)胞通過釋放多種促炎和抗炎細(xì)胞因子來發(fā)揮雙向作用[83,84]。小膠質(zhì)細(xì)胞可以通過介導(dǎo)神經(jīng)炎癥調(diào)節(jié)大腦免疫，并參與突觸的連接和重塑；然而在AD早期小膠質(zhì)細(xì)胞可以介導(dǎo)突觸的異常喪失進(jìn)而促進(jìn)病理進(jìn)程[85]。星形膠質(zhì)細(xì)胞是大腦中存在較為豐富的細(xì)胞，可維持神經(jīng)遞質(zhì)的穩(wěn)態(tài)，引導(dǎo)突觸的形成和成熟，調(diào)節(jié)活性氧和血腦屏障[86~88]。神經(jīng)炎癥和缺血可誘導(dǎo)出兩種不同類型的反應(yīng)性星形膠質(zhì)細(xì)胞，稱為A1和A2反應(yīng)性星形膠質(zhì)細(xì)胞。A1反應(yīng)性星形膠質(zhì)細(xì)胞的上調(diào)可能是有害的，而A2反應(yīng)性星形膠質(zhì)細(xì)胞的上調(diào)可能是有益的[89]。此外，衰老的星形膠質(zhì)細(xì)胞具有神經(jīng)炎性A1樣反應(yīng)性星形膠質(zhì)細(xì)胞的反應(yīng)性表型。除了釋放有效的神經(jīng)毒素外，A1星形膠質(zhì)細(xì)胞還能促進(jìn)新突觸的形成，并導(dǎo)致中樞神經(jīng)系統(tǒng)神經(jīng)元的興奮功能降低。除了星形膠質(zhì)細(xì)胞反應(yīng)性狀態(tài)的改變外，星形膠質(zhì)細(xì)胞中可能還會(huì)發(fā)生其他轉(zhuǎn)錄和功能性變化，這可以解釋正常衰老過程中認(rèn)知能力下降這一現(xiàn)象[90]，而在PD模型中抑制A1星形膠質(zhì)細(xì)胞的活性具有保護(hù)神經(jīng)作用[91]。

研究發(fā)現(xiàn)，在AD中，星形膠質(zhì)細(xì)胞是大腦在生理?xiàng)l件下表達(dá)的主要細(xì)胞，星形膠質(zhì)細(xì)胞參與Aβ攝取和降解[92,93]。在AD早期階段，BACE1活性增加伴隨著BACE2活性的相應(yīng)增加，BACE2主要定位于星形膠質(zhì)細(xì)胞中[94]。在PD中，從神經(jīng)元釋放的α-Syn被星形膠質(zhì)細(xì)胞吸收，進(jìn)而影響其線粒體的完整性并導(dǎo)致神經(jīng)毒性的產(chǎn)生[95~97]。研究發(fā)現(xiàn)星型膠質(zhì)細(xì)胞在神經(jīng)退行性疾病的病理性擴(kuò)散中具有潛在的協(xié)同作用[98]。在HD中，隨著疾病進(jìn)展會(huì)增加相關(guān)星形細(xì)胞的活性，進(jìn)而導(dǎo)致Htt的聚集[99,100]。在ALS中，星形膠質(zhì)細(xì)胞顯示出毒性表型，引起運(yùn)動(dòng)神經(jīng)元變性。Rab31在表皮生長因子受體轉(zhuǎn)運(yùn)至晚期內(nèi)含體的運(yùn)輸中發(fā)揮作用[101]，沉默研究引起的EGFR信號(hào)轉(zhuǎn)導(dǎo)增加可能會(huì)阻礙培養(yǎng)物中星形膠質(zhì)細(xì)胞的完全發(fā)育，從而導(dǎo)致存活的星形膠質(zhì)細(xì)胞百分比降低[102]。

在促炎條件下，智利大學(xué)Quest等[103]通過生物信息學(xué)發(fā)現(xiàn)，反應(yīng)性星形膠質(zhì)細(xì)胞中Rab的內(nèi)吞途徑發(fā)生了改變，其有利于蛋白水解的回收。特別是，Rab4、Rab5和Rab7的蛋白表達(dá)水平發(fā)生變化。另一方面，這種促炎環(huán)境增加了和的表達(dá)，并降低了Rab7-GTP的負(fù)荷。在促炎環(huán)境中，從早期(Rab5)到晚期內(nèi)含體(Rab7)的貨物運(yùn)輸也發(fā)生了變化。通過分析晚期和早期內(nèi)體組分中的低密度脂蛋白LDL (注定要降解的貨物)的分布，研究人員觀察到LDL保留在TNFα刺激的細(xì)胞的外圍，這表明由Rab7所介導(dǎo)的溶酶體降解能力下調(diào)[103]。在神經(jīng)退行性疾病和腦損傷中，星形膠質(zhì)細(xì)胞活化涉及Rab依賴性途徑的分子機(jī)制尚待研究。

6 結(jié)語與展望

本文主要分析了一些Rab蛋白在神經(jīng)類疾病中的運(yùn)輸和信號(hào)傳導(dǎo)中的變化，Rab蛋白的異常表達(dá)、活性改變或定位錯(cuò)誤可能與多種神經(jīng)類疾病如(AD、PD和HD)的致病機(jī)制有關(guān)(表1)。參與內(nèi)吞降解途徑的Rab7A可以調(diào)節(jié)tau蛋白的分泌。Rab11和Rab21可以通過影響B(tài)ACE1或PS1的定位進(jìn)而影響Aβ的產(chǎn)生。Rab35可以促進(jìn)α-syn的分泌。沉默加htt突變蛋白的聚集。在ALS和CMT2B中，Rab7參與調(diào)節(jié)軸突運(yùn)輸以及內(nèi)吞途徑，神經(jīng)營養(yǎng)蛋白的信號(hào)傳導(dǎo)。Rab蛋白主要通過調(diào)節(jié)內(nèi)吞途徑來影響蛋白聚集體的產(chǎn)生。另一方面，神經(jīng)退行性疾病的致病機(jī)制，即線粒體和星形膠質(zhì)細(xì)胞的功能異常也與Rab蛋白水平的改變密切相關(guān)。線粒體功能障礙發(fā)生在神經(jīng)退行性疾病的早期階段，是造成神經(jīng)元死亡的重要原因。線粒體功能障礙的出現(xiàn)和加重可能是由病理過程發(fā)展中涉及的許多因素造成的。研究與受損線粒體自噬調(diào)節(jié)的相關(guān)Rab蛋白并分析Rab蛋白在其中的調(diào)節(jié)途徑對(duì)神經(jīng)退行性疾病的早期診斷將會(huì)有很大幫助。

星形膠質(zhì)細(xì)胞在神經(jīng)退行性疾病中的作用機(jī)制是目前的研究熱點(diǎn)，Rab蛋白在其中的作用尚不清楚。星形膠質(zhì)細(xì)胞對(duì)于維持腦穩(wěn)態(tài)和保護(hù)神經(jīng)元至關(guān)重要。星形膠質(zhì)細(xì)胞中的溶酶體降解能力不足，與包括PD在內(nèi)的各種神經(jīng)退行性疾病的發(fā)病機(jī)理有關(guān)。阻止或者減少A1反應(yīng)性星形膠質(zhì)細(xì)胞的形成可以減緩神經(jīng)退行性疾病的病理進(jìn)程。在成年嚙齒動(dòng)物的大腦中，僅在神經(jīng)膠質(zhì)纖維酸性蛋白陽性星形膠質(zhì)細(xì)胞中表達(dá)[101]。Rab蛋白作為星型膠質(zhì)細(xì)胞的生物標(biāo)志物，具有作為神經(jīng)退行性疾病診斷工具的巨大潛力。

表1 神經(jīng)退行性疾病中的Rab蛋白及其功能

盡管已經(jīng)非常深入地研究了幾種Rab蛋白，但是Rab蛋白家族仍有巨大的研究潛力，Rab蛋白在中樞神經(jīng)系統(tǒng)不同組織中的特殊作用至關(guān)重要。神經(jīng)退行性疾病是一些常見功能障礙導(dǎo)致的具有不同病理特征的疾病。Rab蛋白在不同的神經(jīng)退行性疾病中顯示出不同的調(diào)節(jié)作用，但是目前尚不清楚是Rab蛋白的變化引起功能障礙還是功能障礙導(dǎo)致Rab蛋白水平發(fā)生變化。發(fā)現(xiàn)和研究這些潛在的常見機(jī)制可以使我們更加了解神經(jīng)元存活的基本要求，為深入探究這幾種神經(jīng)類疾病的病理學(xué)機(jī)制奠定基礎(chǔ)，同時(shí)為開發(fā)有效的治療策略開辟新的道路。

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The roles of Rab protein family in neurological diseases

Anping Wu, Hong Qing, Zhenzhen Quan

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The intracellular membrane trafficking is a complicated pathway network. Rab GTPases are key regulators of membrane trafficking that are generally considered as specific markers and indicators of various organelles and membrane trafficking in endocytic and secretory pathways. Dysfunction in axonal and endosomal transport related to Rab proteins is one of the most important causes of neurodegenerative diseases. In this review, we mainly introduce how the Rab proteins change in different neurodegenerative diseases and their regulatory roles in the pathological mechanisms of related diseases. We also discuss the relationships between mitochondrial and glial cell dysfunctions and Rab proteins. Further exploration of the regulatory roles of Rab proteins will shed lights on revealing the pathogenic mechanisms of neurological diseases and providing potential targets for the early diagnosis and treatment of neurological diseases.

Rab proteins; neurological diseases; membrane trafficking; mitochondria; astrocytes

2020-11-17;

2021-01-06

國家自然科學(xué)基金項(xiàng)目(編號(hào)：81701260)資助[Supported by the National Natural Science Foundation of China (No. 81701260)]

吳安平，在讀碩士研究生，專業(yè)方向：生物工程。E-mail: 18801361945@163.com

全貞貞，博士，副研究員，研究方向：阿爾茨海默病的分子機(jī)制。E-mail: qzzbit2015@bit.edu.cn

10.16288/j.yczz.20-318

2021/1/13 13:37:12

URI: https://kns.cnki.net/kcms/detail/11.1913.R.20210112.1032.001.html

(責(zé)任編委: 史岸冰)