張 麗，張連峰,2*

(1.中國(guó)醫(yī)學(xué)科學(xué)院，醫(yī)學(xué)實(shí)驗(yàn)動(dòng)物研究所，北京協(xié)和醫(yī)學(xué)院比較醫(yī)學(xué)中心，衛(wèi)計(jì)委人類疾病比較醫(yī)學(xué)重點(diǎn)實(shí)驗(yàn)室，北京 100021； 2．中國(guó)醫(yī)學(xué)科學(xué)院神經(jīng)科學(xué)中心，北京 100730)

研究進(jìn)展

肌萎縮側(cè)索硬化癥相關(guān)基因突變與疾病動(dòng)物模型

張 麗1，張連峰1,2*

(1.中國(guó)醫(yī)學(xué)科學(xué)院，醫(yī)學(xué)實(shí)驗(yàn)動(dòng)物研究所，北京協(xié)和醫(yī)學(xué)院比較醫(yī)學(xué)中心，衛(wèi)計(jì)委人類疾病比較醫(yī)學(xué)重點(diǎn)實(shí)驗(yàn)室，北京 100021； 2．中國(guó)醫(yī)學(xué)科學(xué)院神經(jīng)科學(xué)中心，北京 100730)

肌萎縮側(cè)索硬化癥是一種累進(jìn)性神經(jīng)退行疾病，以上、下運(yùn)動(dòng)神經(jīng)元選擇性退化和凋亡為特征，引發(fā)癱瘓、最終導(dǎo)致死亡。大量引發(fā)ALS的基因突變被鑒定出，包括FUS/TLS、EPHA4、SS18L1、ATXN2 和C9ORF72等基因，這些基因突變的發(fā)現(xiàn)拓寬了RNA調(diào)節(jié)參與ALS病理生成的理解。本文對(duì)家族性ALS相關(guān)的基因突變及現(xiàn)有的ALS嚙齒類動(dòng)物模型進(jìn)行總結(jié)概括。

肌萎縮側(cè)索硬化癥；基因突變；動(dòng)物模型

肌萎縮側(cè)索硬化癥(amyotrophic lateral sclerosis，ALS)也稱為“葛雷克氏癥”，是一種累進(jìn)性神經(jīng)退行疾病，以控制肌肉收縮的一種神經(jīng)元即上、下運(yùn)動(dòng)神經(jīng)元選擇性退化和凋亡為特征，引發(fā)癱瘓、最終導(dǎo)致死亡。ALS分為家族型和分散性兩類，家族型ALS(fALS)約占10%，散發(fā)性ALS (sALS) 占90%。目前已找到多種引發(fā)ALS的基因突變，僅占這些病例的20%～30%左右。但大部分家族型和是絕大部分分散病例的病因仍是未知，可能與神經(jīng)突觸內(nèi)谷氨酸的興奮毒性、氧化應(yīng)激、神經(jīng)營(yíng)養(yǎng)因子、自身免疫反應(yīng)、重金屬中毒、慢病毒感染等有關(guān)。

ALS目前缺少有效的治療方法。發(fā)現(xiàn)新的致病基因、易感基因，尋找不同致病基因?qū)е翧LS的共同機(jī)制和治療靶點(diǎn)等仍然是目前研究的熱點(diǎn)。本文就目前發(fā)現(xiàn)的ALS相關(guān)基因突變和動(dòng)物模型情況作如下總結(jié)。

1 參與ALS病理發(fā)生的基因

從1995年發(fā)現(xiàn)SOD1基因突變是家族型ALS的致病基因以來[1]，ALS致病基因的發(fā)現(xiàn)越來越多，包括近5年發(fā)現(xiàn)的EPHA4、SS18L1和ATXN2等。表1列舉了ALS相關(guān)基因，共計(jì)27種，其中，SOD1、C9ORF72、FUS和TARDBP與ALS關(guān)系最為密切，SOD1在家族型ALS中占了15%，C9ORF72重復(fù)核酸擴(kuò)增在家族型ALS中占了45%，在散發(fā)性ALS中占了10%，F(xiàn)US和TARDBP在家族型ALS中比例均可達(dá)4%；SETX、VAPB、ANG、OPTN、SQSTM1等比較罕見，僅與少數(shù)ALS相關(guān)，見圖1。仍有一些分子流行病研究發(fā)現(xiàn)的ALS相關(guān)基因可作為尚未確定基因。

圖1 家族型ALS致病基因比例Fig.1 The percentage of four familial ALS disease-causing genes and other genes

表1 參與 ALS病理發(fā)生的基因

續(xù)表1

基因Genes基因功能Genefunction染色體Chromosome突變Mutations家族性/%fALS散發(fā)性/%sALS參考文獻(xiàn)ReferencesTARDBP/TDP-43DNA/RNA結(jié)合蛋白，證據(jù)明確顯示TDP-43蛋白異常沉積與ALS病理相關(guān)。DNA/RNAbindingproteins，thepathologicaccumulationofTDP?43isnowwellrecognizedtocontributetothepa?thologyofALS．1p362239402～04[7]ARHGEF28該蛋白可結(jié)合神經(jīng)絲蛋白mRNA，可能參與了ALS神經(jīng)絲蛋白聚集體的形成。TheencodedproteininteractswithneurofilamentmRNAandmaybeinvolvedintheformationofALSneurofilamentaggregates．5q132---[8]SETX該蛋白具有DNA/RNA解旋酶功能域，參與RNA剪切過程?；蛲蛔兒鸵粋€(gè)常染色體顯性遺傳的青少年ALS相關(guān)。ThisproteincontainsaDNA/RNAhelicasedomainwhichsuggeststhatitmaybeinvolvedinbothDNAandRNAprocessing．MutationsinthisgenehavebeenassociatedwithanautosomaldominantformofjuvenileALS．9q34137罕見Rare[9]ATXN2ATXN2蛋白N端包含一個(gè)14～31殘基多谷氨酰胺區(qū)域，病理?xiàng)l件擴(kuò)增至32～200個(gè)。多谷氨酰胺長(zhǎng)度增加的個(gè)體對(duì)ALS易感。TheN?terminalregionoftheproteincontainsapolyglu?taminetractof14-31residuesthatcanbeexpandedinthepathogenicstateto32-200residues．IntermediatelengthexpansionsofthistractincreasesusceptibilitytoALS．12q2412CAG重復(fù)擴(kuò)增CAGrepeatexpansion47-[10，11]PFN1參與肌動(dòng)蛋白的聚合-解聚動(dòng)態(tài)平衡調(diào)節(jié)。該基因的缺失與Miller?Dieker綜合癥相關(guān)，所編碼的蛋白質(zhì)也可能在亨廷頓病中發(fā)揮作用。Theencodedproteinplaysanimportantroleinactindy?namicsbyregulatingactinpolymerization．DeletionofthisgeneisassociatedwithMiller?Diekersyndrome，andtheencodedproteinmayalsoplayaroleinHuntingtondisease．17p1324--[12]SS18L1SS18L1鈣敏感的反式激活因子，參與表觀遺傳控制和染色質(zhì)重塑。SS18L1突變與ALS相關(guān)。Thisgeneencodesacalcium?responsivetransactivatorwhichisanessentialsubunitofaneuron?specificchroma?tin?remodelingcomplex．Mutationsinthisgenearein?volvedinALS．20q1333---[13，14]C9ORF72與RAB蛋白相互作用參與自噬和內(nèi)吞，具有2～22個(gè)或700～1600個(gè)拷貝的GGGGCC六核苷酸重復(fù)擴(kuò)增突變與ALS或額顳癡呆(FTD)相關(guān)。C9ORF72hasbeenshowntointeractwithRabproteinsthatareinvolvedinautophagyandendocytictransport．Ex?pansionofaGGGGCCrepeatfrom2-22copiesto700-1600copiesintranscriptsfromthisgeneisassociatedwithALSandFTD(frontotemporaldementia)．9p212GGGGCC重復(fù)擴(kuò)增GGGGCCrepeatexpansion4510[15]OPTNOPTN可與huntingtin蛋白、轉(zhuǎn)錄因子3A以及RAB8蛋白相互作用，具有激活TNFa和Fas配體通路介導(dǎo)凋亡和炎癥，基因突變導(dǎo)致家族型青光眼和ALS。OPTNinteractionswithhuntingtin，RAB8andtranscriptionfactorIIIAproteins．Itmayutilizetumornecrosisfactor?al?phaorFas?ligandpathwaystomediateapoptosisandin?flammation．OPTNmutationsareassociatedwithfamilialglaucomaandALS．10p133罕見Rare-[16]

續(xù)表1

基因Genes基因功能Genefunction染色體Chromosomes突變Mutations家族性/%fALS散發(fā)性/%sALS參考文獻(xiàn)ReferencesUBQLN2蛋白質(zhì)泛素化與降解。Thisproteinisthoughttofunctionallylinktheubiquitina?tionmachinerytotheproteasometoaffectinvivoproteindegradation．Xp11215--[17]SQSTM1可與泛素結(jié)合并調(diào)節(jié)NF?KB信號(hào)通路。SQSTM1bindsubiquitinandregulatesactivationofthenu?clearfactorkappa?B(NF?kB)signalingpathway．5q353罕見Rare[18]VCP參與高爾基體分選和蛋白質(zhì)泛素化與降解。TheencodedproteinplaysaroleinGolgisorting，proteinubiquitinationanddegradation．9p1334--[19]ALS2/ALSIN參與膜泡運(yùn)輸，調(diào)節(jié)內(nèi)吞。Thisproteinisinvolvedinvesiculartransportandfunctionsasamodulatorforendosomaldynamics．2q33119--[20]HNRNPA2B1核糖核蛋白類，與mRNA加工、代謝和運(yùn)輸有關(guān)。Thisgeneencodesheterogeneousnuclearribonucleoproteins(hnRNPs)andinfluencespre?mRNAprocessing，aswellasotheraspectsofmRNAmetabolismandtransport．7p152---[21，22]HNRNPA1核糖核蛋白類，與mRNA加工、代謝和運(yùn)輸有關(guān)。Thisgeneencodesheterogeneousnuclearribonucleoproteins(hnRNPs)thatassociatewithpre?mRNAsinthenucleusandinfluencespre?mRNAprocessing，aswellasotheraspectsofmRNAmetabolismandtransport．12q1313---[22]CHMP2B參與膜泡運(yùn)輸。CHMP2Bisinvolvedinvesiculartransport．3p112---[23]ELP3ELP3是組蛋白乙酰轉(zhuǎn)移酶復(fù)合物的催化亞基，和RNA合成延長(zhǎng)，投射神經(jīng)元成熟有關(guān)。ELP3isthecatalyticsubunitofthehistoneacetyltransferaseelongatorcomplex，whichcontributestotranscriptelongationandalsoregulatesthematurationofprojectionneurons．8p211---[24]ANGRNA酶家族成員，促進(jìn)tRNA水解進(jìn)而導(dǎo)致蛋白合成下降，可調(diào)節(jié)新生血管形成和運(yùn)動(dòng)神經(jīng)元軸突生長(zhǎng)。Thisgeneencodesribonuclease，RNaseAfamily．Ithydro?lyzescellulartRNAsresultingindecreasedproteinsynthe?sis．Itisanexceedinglypotentmediatorofnewbloodvesselformationandmotorneuronaxonoutgrowth．14q11218罕見Rare[20]SPG11參與細(xì)胞間物質(zhì)轉(zhuǎn)運(yùn)，與神經(jīng)元軸突生長(zhǎng)有關(guān)。Theproteinisinvolvedinintercellulartransportandisre?latedtoaxonoutgrowth．15q211---[20]DCTN1可與細(xì)胞內(nèi)微管結(jié)合驅(qū)動(dòng)軸突運(yùn)輸。Dynactinbindstomicrotubulestodriveaxonaltransport．2p131---[25]NEFH參與神經(jīng)元細(xì)胞骨架的形成。Theproteinisinvolvedintheformationofneuronalcy?toskeleton．22q122---[20]VAPB參與細(xì)胞間物質(zhì)轉(zhuǎn)運(yùn)，與神經(jīng)元軸突生長(zhǎng)有關(guān)。Theproteinisinvolvedinintercellulartransportandisre?latedtoaxonoutgrowth．20q13322罕見Rare[20]

注: -, 不明確；fALS，家族性脊髓側(cè)索硬化癥；ALS，脊髓側(cè)索硬化癥。

Note. -, unclear; fALS, familial amyotrophic lateral sclerosis; ALS, amyotrophic lateral sclerosis.

2 RNA代謝異常是ALS主要機(jī)制？

研究表明，ALS是通過異常的蛋白脂代謝如ER應(yīng)激和自噬以及RNA剪切加工過程介導(dǎo)的。而在所有的非SOD1介導(dǎo)的ALS疾病均有RNA剪切過程參與。目前發(fā)現(xiàn)的參與ALS病理發(fā)生的基因有30種左右，涉及細(xì)胞表面受體、RNA剪切、蛋白質(zhì)合成到軸突轉(zhuǎn)運(yùn)等多個(gè)方面。但是，涉及RNA剪切、延伸和代謝的基因占了主要部分，其中C9ORF72突變導(dǎo)致的ALS疾病在家族性ALS病例的中的比例最高，與RNA代謝的關(guān)系也最為密切。由于C9ORF72剪切體1的第一外顯子E1a和剪切體3的第一外顯子E1b之間有GGGGCC六個(gè)堿基的重復(fù)序列(hexanucleotide repeat expansion，HRE)，HER長(zhǎng)短在人群中具有多態(tài)性，正常人群中GGGGCC重復(fù)數(shù)一般在30個(gè)以下，高于30個(gè)重復(fù)會(huì)有發(fā)生額顳葉癡呆(FTD)或ALS的可能，ALS患者中拷貝數(shù)可高達(dá)1 600個(gè)。盡管C9ORF72的致病機(jī)制仍然處于初始階段，但是目前可推測(cè)HER有二種可能機(jī)制參與FTD或ALS。其一是HRE結(jié)構(gòu)導(dǎo)致C9ORF72轉(zhuǎn)錄子在細(xì)胞內(nèi)的積累，并可能與DNA形成RNA/DNA 雜交環(huán)(R-loop)引起RNA毒性。第二種可能是HRE結(jié)構(gòu)可能導(dǎo)致一種叫做不需要ATG的翻譯(repeat-associated non-ATG (RAN) translation)GGGGCC重復(fù)可以編碼甘胺酸/精氨酸或脯氨酸/精氨酸的多肽，這兩種多肽都有細(xì)胞毒性。C9ORF72第一外顯子后的GGGGCC多拷貝重復(fù)，造成RNA的異常積累和定位。

此外，F(xiàn)US、TARDB、SETX、ATXN2、ARHGEF28、ELP3、HNRPA2B1和HNRPA1等8個(gè)基因在ALS所占比例次于C9ORF72，也與RNA代謝相關(guān)。FUS和TARDBP是一個(gè)多功能的DNA和RNA結(jié)合蛋白，參與RNA轉(zhuǎn)錄、選擇性剪接及mRNA穩(wěn)定性調(diào)節(jié)。SETX有DNA/RNA解旋酶功能域，參與tRNA和核內(nèi)小RNA的剪切。ANG 屬于RNA酶，ATXN2突變可以增加TARDBP毒性。ARHGEF28是Rho信號(hào)激活單白，但可以結(jié)合神經(jīng)絲蛋白mRNA 并引起其降解，ELP3參與RNA合成延長(zhǎng)。HNRPA2B1和HNRPA1編碼不均一型核糖核蛋白(heterogeneous nuclear ribonucleoprotein，hnRNP)是多功能RNA結(jié)合蛋白，可調(diào)節(jié)前體mRNA(pre-mRNA)分子的選擇性剪接以及mRNA轉(zhuǎn)運(yùn)、翻譯和穩(wěn)定性。因此RNA代謝異?？赡苁茿LS的核心機(jī)制之一。

3 ALS動(dòng)物模型

ALS動(dòng)物模型是研究ALS的病因、病理、發(fā)病機(jī)制和治療的重要工具。目前建立ALS的嚙齒類動(dòng)物模型主要是SOD1、TDP-43、VCP、FUS、ALSIN等基因的不同突變體和采用不同啟動(dòng)子的轉(zhuǎn)基因大小鼠或基因敲除小鼠，還包括Wobbler小鼠自發(fā)突變ALS易感品系，以及免疫原誘發(fā)的豚鼠ALS模型(表2)。自發(fā)突變ALS易感品系Wobbler小鼠是50年前建立的ALS模型，現(xiàn)在仍然廣泛使用。hmSOD1-G93A突變基因轉(zhuǎn)基因小鼠是目前應(yīng)用最廣泛的ALS模型[27]，比較客觀的反映氧化應(yīng)激對(duì)運(yùn)動(dòng)神經(jīng)元的損傷機(jī)制。

4 ALS疾病動(dòng)物模型展望

ALS病因多樣，機(jī)制復(fù)雜，目前所建立的基因修飾模型和誘導(dǎo)模型尚不能全方位的反映ALS的病理機(jī)制，這也成為ALS治療研究的限制之一。一方面現(xiàn)有的模型品系僅涉及有限的基因，大多致病基因包括新發(fā)現(xiàn)的ALS致病基因比如C9ORF72、ARHGEF28尚未建立模型，這些基因可能反映不同致病機(jī)制。另一方面，已經(jīng)建立的SOD1、TDP-43、FUS等基因在野生型基因高表達(dá)時(shí)也會(huì)引起神經(jīng)毒性[28,31,32], 所以轉(zhuǎn)基因模型不能完全反映基因突變的特點(diǎn)。相對(duì)于轉(zhuǎn)基因隨機(jī)插入，基因敲入是實(shí)現(xiàn)基因穩(wěn)定過表達(dá)的一種有效工具。利用CRISPR/Cas9技術(shù)可以實(shí)現(xiàn)外源基因的定點(diǎn)敲入，使遺傳背景更為簡(jiǎn)單，實(shí)驗(yàn)操作更加精準(zhǔn)、高效。此外，很多致病基因表達(dá)的蛋白具備多個(gè)功能域，可以和其他多種因子相互作用，而且基因敲除和點(diǎn)突變對(duì)細(xì)胞作用也是不同的，基因敲除ALS模型不能完全反映基因突變的致病機(jī)制，因此在未來的研究中，需要以突變的基因敲入為主，制作更能反映致病機(jī)制的ALS模型。

表2 ALS嚙齒類模型

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Amyotrophiclateralsclerosis-associatedgenemutationsandALSanimalmodels

ZHANG Li1， ZHANG Lian-feng1,2*

(1.Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, Key Laboratory of Human Disease Comparative Medicine, National Health and Family Planning Commission of P.R.C, Beijing 100021，China； 2.Neuroscience Center, Chinese Academy of Medical Sciences, Beijing 100730，China)

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by a selective loss of upper and lower motor neurons that lead to paralysis and even death. Mutations in a large number of genes, includingFUS/TLS,EPHA4,SS18L1,ATXN2 andC9ORF72, are identified to the casual genes of ALS, which broadens our understanding of the role of RNA modulation in ALS pathogenesis. This review summarized ALS-associated genes and the related ALS rodent models.

Amyotrophic lateral sclerosis; Gene mutation; Animal model

R-33

A

1671-7856(2017) 10-0089-07

10.3969.j.issn.1671-7856. 2017.10.018

2017-03-01

國(guó)家自然科學(xué)基金(81571222)；中央級(jí)公益科研院所基本科研業(yè)務(wù)費(fèi)(2016ZX310039)。

張麗(1981-)，女，博士，研究方向：比較醫(yī)學(xué)。E-mail: zhangl@cnilas.org

張連峰，男，研究員，博士，研究方向：比較醫(yī)學(xué)。E-mail: zhanglf@cnilas.org