黃嘯君 曹立

腦組織鐵沉積性神經(jīng)變性病遺傳學(xué)研究進(jìn)展

黃嘯君 曹立

腦組織鐵沉積性神經(jīng)變性病是以腦組織鐵代謝異常、中樞神經(jīng)系統(tǒng)過量鐵沉積為特征的神經(jīng)變性病.常見臨床癥狀為不同類型運(yùn)動(dòng)障礙,同時(shí)合并不同程度錐體束、小腦、周圍神經(jīng)系統(tǒng)、自主神經(jīng)系統(tǒng)、精神認(rèn)知和視覺障礙,具有高度臨床異質(zhì)性.目前共明確10種亞型的10種致病基因,分別為PANK2、COASY、PLA2G6、C19orf12、FA2H、WDR45、ATP13A2、FTL、CP、DCAF17.發(fā)病機(jī)制涉及線粒體功能障礙、氧化應(yīng)激損傷、脂質(zhì)代謝障礙、鐵沉積和自噬障礙等.腦組織鐵沉積性神經(jīng)變性病可能與多種神經(jīng)變性病如帕金森病、額顳葉癡呆、肌萎縮側(cè)索硬化癥等存在共同的發(fā)病機(jī)制.

神經(jīng)變性疾病; 鐵代謝障礙; 遺傳學(xué); 綜述

腦組織鐵沉積性神經(jīng)變性病(NBIA)是一組以腦組織鐵代謝異常和過量鐵沉積為特征的神經(jīng)變性病,過量鐵沉積于蒼白球、黑質(zhì)及其相鄰部位而致病[1].臨床表現(xiàn)具有高度異質(zhì)性,最常見癥狀為不同類型運(yùn)動(dòng)障礙,包括進(jìn)行性加重的運(yùn)動(dòng)減退和(或)運(yùn)動(dòng)過度,亦可合并不同程度錐體束、小腦、周圍神經(jīng)系統(tǒng)、自主神經(jīng)系統(tǒng)、精神認(rèn)知、視覺功能障礙.腦組織鐵沉積性神經(jīng)變性病系神經(jīng)系統(tǒng)遺傳性疾病,隨著分子遺傳學(xué)技術(shù)的發(fā)展,迄今已明確10種亞型的致病基因,致病機(jī)制涉及線粒體代謝、脂質(zhì)代謝和細(xì)胞自噬等;仍有約20%患者未明確致病基因.本文擬就目前已明確的腦組織鐵沉積性神經(jīng)變性病各亞型遺傳學(xué)特點(diǎn)(表1)及相關(guān)研究進(jìn)展進(jìn)行闡述.

表1 腦組織鐵沉積性神經(jīng)變性病各亞型遺傳學(xué)和臨床特點(diǎn)Table 1. Genetic and clinical features of NBIA

一、泛酸激酶相關(guān)性神經(jīng)變性病

PANK2基因突變導(dǎo)致的泛酸激酶相關(guān)性神經(jīng)變性病[PKAN,在線人類孟德爾遺傳數(shù)據(jù)庫(OMIM)編號(hào):234200]是最常見亞型,占所有腦組織鐵沉積性神經(jīng)變性病的35%～50%[2].PANK2基因定位于20p13,包含7個(gè)外顯子,相對(duì)分子質(zhì)量1.85X103,編碼PANK2蛋白.泛酸激酶的主要作用是催化ATP依賴的泛酸磷酸化,維生素B5在其作用下磷酸化為4?磷酸泛酰胺,這一過程是輔酶A(CoA)生物合成的第一步,輔酶A在體內(nèi)脂肪酸、糖和氨基酸代謝中發(fā)揮關(guān)鍵作用.PANK2基因突變可以導(dǎo)致泛酸激酶活性缺失,使輔酶A生物合成受阻以及合成底物N?泛酰半胱氨酸和游離半胱氨酸蓄積,半胱氨酸可以螯合鐵離子,故可以造成異常鐵沉積.此外,游離半胱氨酸在鐵離子存在的情況下可以發(fā)生氧化反應(yīng)并產(chǎn)生活性氧(ROS),并通過脂質(zhì)過氧化導(dǎo)致廣泛性氧化損傷和細(xì)胞死亡[2].PANK2基因參與輔酶A的生物合成,其與輔酶A和?；o酶A(acyl?CoA)之間存在負(fù)性調(diào)控,PANK2基因還可以感受輔酶A表達(dá)變化,進(jìn)而調(diào)節(jié)線粒體和胞質(zhì)代謝[3],由此可以解釋部分基因突變雖未直接引起酶活性改變卻同樣導(dǎo)致臨床表型出現(xiàn).此外,研究顯示,PANK2蛋白存在于線粒體[4].動(dòng)物實(shí)驗(yàn)顯示,PANK2基因突變的纖維母細(xì)胞[4]以及PANK2基因敲除小鼠和果蠅模型存在線粒體功能缺陷,包括線粒體膜電位降低、線粒體腫脹和線粒體嵴改變等[5],其中,線粒體膜電位降低可以影響線粒體運(yùn)動(dòng)速度、融合和運(yùn)輸.PANK2基因突變還可以引起線粒體特異性脂肪酸合成途徑破壞,此合成途徑對(duì)線粒體膜的組裝和功能維持至關(guān)重要[6].研究顯示,PANK2基因突變可以使脂質(zhì)代謝失調(diào)[6].PANK2基因突變除可以引起泛酸激酶相關(guān)性神經(jīng)變性病外,還可以導(dǎo)致低β脂蛋白血癥?棘紅細(xì)胞增多癥?視網(wǎng)膜色素變性?蒼白球變性綜合征(HARP),二者在臨床表型上存在一定重疊,提示PANK2基因突變與脂肪合成缺陷相關(guān)[6].

泛酸激酶相關(guān)性神經(jīng)變性病是常染色體隱性遺傳性疾病,錯(cuò)義突變?yōu)樽钪饕蛔冾愋?常見點(diǎn)突變有c.1231G>A和c.1253C>T,此外還包括堿基缺失、重復(fù)突變、插入、剪切位點(diǎn)突變等[7].某些突變引起的臨床表型輕微[8?9].泛酸激酶相關(guān)性神經(jīng)變性病的臨床表型包括典型和非典型,其中,典型也稱早發(fā)型,多于6歲前發(fā)病[8,10],表現(xiàn)為錐體束征和錐體外系癥狀,如步態(tài)異常、肌張力障礙、帕金森樣癥狀、共濟(jì)失調(diào)等,同時(shí)合并精神異常[8,11?12]和視覺障礙等,病情進(jìn)展迅速,通常于發(fā)病15年內(nèi)喪失行走能力,20歲前生活不能自理;而非典型發(fā)病年齡較晚,病情進(jìn)展緩慢,運(yùn)動(dòng)功能受累相對(duì)較輕[13],認(rèn)知功能障礙和精神異常是常見癥狀,表現(xiàn)為抑郁、情緒不穩(wěn)、沖動(dòng)性提高等.研究顯示,部分非典型泛酸激酶相關(guān)性神經(jīng)變性病患者表現(xiàn)出年齡依賴性,青少年或成年早期發(fā)病的患者多有肌張力障礙表現(xiàn),帕金森樣癥狀通常出現(xiàn)于發(fā)病年齡較晚的患者[14].

二、輔酶A合成酶相關(guān)性神經(jīng)變性病

COASY基因突變導(dǎo)致的輔酶A合成酶相關(guān)性神經(jīng)變性病(CoPAN,OMIM編號(hào):609855)是繼泛酸激酶相關(guān)性神經(jīng)變性病之后的第2個(gè)影響輔酶A的腦組織鐵沉積性神經(jīng)變性病亞型,呈常染色體隱性遺傳[15].COASY基因位于與PANK2基因相同的代謝途徑中,是催化輔酶A合成的最后2個(gè)步驟的雙功能酶[16?17].COASY蛋白包含2個(gè)催化激酶結(jié)構(gòu)域,均具有線粒體定位信號(hào)、調(diào)節(jié)區(qū)和結(jié)構(gòu)域.COASY蛋白定位于線粒體基質(zhì)[15?16],包括2種異構(gòu)體,較長的β?異構(gòu)體具有腦組織特異性,且具有額外富含脯氨酸的蛋白質(zhì)相互作用結(jié)構(gòu)域,但在酶活性上與替他組織普遍存在的α?異構(gòu)體無明顯差異[18].

突變的COASY蛋白在體外無活性,而在輔酶A合成酶相關(guān)性神經(jīng)變性病患者和正常對(duì)照纖維母細(xì)胞中輔酶A水平正常[15],表明殘留的COASY蛋白在體內(nèi)仍具有維持輔酶A水平的功能,或可能存在其他未知途徑替代輔酶A合成.

COASY基因和PANK2基因在相同代謝途徑中發(fā)揮作用表明,泛酸激酶相關(guān)性神經(jīng)變性病和輔酶A合成酶相關(guān)性神經(jīng)變性病可能具有共同發(fā)病機(jī)制,如?；o酶A和脂質(zhì)合成減少導(dǎo)致線粒體功能障礙等.

臨床表現(xiàn)方面,輔酶A合成酶相關(guān)性神經(jīng)變性病與典型泛酸激酶相關(guān)性神經(jīng)變性病存在相似之處[15]:患者多于兒童早期出現(xiàn)步態(tài)異常和認(rèn)知功能障礙,此后逐漸進(jìn)展為痙攣性肌無力、口下頜肌張力障礙、帕金森樣肌強(qiáng)直、精神癥狀和軸索性周圍神經(jīng)病;二者不同之處是,輔酶A合成酶相關(guān)性神經(jīng)變性病患者眼底鏡和視覺誘發(fā)電位(VEP)檢查正常,且無視網(wǎng)膜病變.

三、磷脂酶A2相關(guān)性神經(jīng)變性病

PLA2G6基因突變致磷脂酶A2相關(guān)性神經(jīng)變性病(PLAN,OMIM編號(hào):256600/610217)是第2位臨床常見亞型[19?20],約占所有腦組織鐵沉積性神經(jīng)變性病的20%,呈常染色體隱性遺傳[20?21].該基因編碼鈣非依賴型磷脂酶A2?β蛋白,包含806個(gè)氨基酸,相對(duì)分子質(zhì)量88X103.PLA2G6基因突變可以導(dǎo)致3種臨床表型,即典型嬰兒神經(jīng)軸索營養(yǎng)不良(INAD)、非典型嬰兒神經(jīng)軸索營養(yǎng)不良和PLA2G6相關(guān)性肌張力障礙?帕金森綜合征(PLAN?DP),其中,典型嬰兒神經(jīng)軸索營養(yǎng)不良是最常見類型,通常于嬰兒期和兒童早期發(fā)病,表現(xiàn)為進(jìn)展迅速的精神運(yùn)動(dòng)發(fā)育遲滯或倒退,繼而出現(xiàn)肌無力,嚴(yán)重軀干肌張力降低,小腦共濟(jì)失調(diào),腱反射減弱或消失,視神經(jīng)萎縮致視力障礙、斜視、眼震[21];非典型嬰兒神經(jīng)軸索營養(yǎng)不良通常于兒童期發(fā)病,發(fā)病年齡1.50～6.50歲,臨床表現(xiàn)較典型嬰兒神經(jīng)軸索營養(yǎng)不良多樣、進(jìn)展相對(duì)緩慢,首發(fā)癥狀和主要表現(xiàn)為小腦共濟(jì)失調(diào)致步態(tài)異常,伴視神經(jīng)萎縮、斜視、眼震、癲發(fā)作、構(gòu)音障礙、神經(jīng)精神癥狀(如情緒不穩(wěn)、多動(dòng)、注意力下降、沖動(dòng)等)、痙攣性截癱,部分患者以肌張力障礙為主要表現(xiàn);PLA2G6相關(guān)性肌張力障礙?帕金森綜合征通常于青少年期或成年早期發(fā)病,主要表現(xiàn)為帕金森樣癥狀、肌張力障礙、認(rèn)知功能障礙和精神行為異常,部分患者伴錐體束征、眼球活動(dòng)障礙、自主神經(jīng)功能障礙、肌陣攣、癲發(fā)作等.

磷脂酶A2(PLA2)家族包括20余種蛋白質(zhì),分為4種類型,即分泌型磷脂酶A2(sPLA2)、鈣依賴型磷脂酶A2、血小板活化因子乙酰水解酶和鈣非依賴型磷脂酶A2[22].腦組織中約70%活性磷脂酶A2由PLA2G6基因編碼[23].盡管PLA2G6基因突變致病主要累及中樞神經(jīng)系統(tǒng),但鈣非依賴型磷脂酶A2在全身各組織中均有表達(dá)[24].PLA2G6基因主要表達(dá)于線粒體[25],對(duì)維持線粒體功能具有一定作用[26],亦表達(dá)于細(xì)胞核核膜和靈長類動(dòng)物腦組織軸突末端[27].PLA2G6蛋白可以水解甘油磷脂以產(chǎn)生溶血磷脂和游離脂肪酸,其中,游離脂肪酸(如白三烯和前列腺素等)下游代謝產(chǎn)物具有特定的細(xì)胞功能并參與多種信號(hào)轉(zhuǎn)導(dǎo),包括細(xì)胞膜重塑、脂肪酸氧化、細(xì)胞生長和凋亡[22];溶血磷脂也在信號(hào)轉(zhuǎn)導(dǎo)中起一定作用,如參與血小板活化因子生成.細(xì)胞膜完整性依靠磷脂再循環(huán)和內(nèi)環(huán)境穩(wěn)態(tài),故磷脂酶活性對(duì)保持細(xì)胞膜完整性至關(guān)重要,而PLA2G6蛋白介導(dǎo)的神經(jīng)退行性變系細(xì)胞膜重塑、脂肪酸氧化障礙和磷脂結(jié)構(gòu)破壞所致.線粒體多不飽和脂肪酸如心磷脂對(duì)活性氧極為敏感.PLA2G6蛋白在過氧化氫處理的細(xì)胞中對(duì)細(xì)胞膜親和力增加,導(dǎo)致其自身活性增加和游離脂肪酸釋放增加[28].細(xì)胞異常產(chǎn)生的活性氧可以螯合PLA2G6基因至線粒體,是阻止細(xì)胞凋亡的機(jī)制之一[26],但超微結(jié)構(gòu)已出現(xiàn)線粒體功能缺陷.線粒體呼吸鏈和相關(guān)去極化解耦聯(lián)作用可以導(dǎo)致線粒體內(nèi)PLA2G6蛋白活化,使游離脂肪酸蓄積[29],繼而通過細(xì)胞色素C釋放而引起細(xì)胞凋亡[30];而PLA2G6蛋白活性降低可以使此過程失調(diào),導(dǎo)致功能異常的線粒體清除障礙.此外,PLA2G6蛋白在維持細(xì)胞膜穩(wěn)態(tài)中發(fā)揮重要作用.PLA2G6蛋白功能缺陷可以導(dǎo)致線粒體內(nèi)膜和軸突末端退行性變[31].軸索和(或)細(xì)胞器包膜完整性破壞可以導(dǎo)致軸突傳導(dǎo)障礙和細(xì)胞成分在軸突遠(yuǎn)端蓄積,從而發(fā)生彌漫性軸索阻滯和變性[32].

迄今發(fā)現(xiàn)的PLA2G6基因突變分布于基因全長,無突變熱點(diǎn)可以導(dǎo)致酶活性降低[33],且降低程度與病情嚴(yán)重程度相關(guān).PLA2G6基因全部缺失可以導(dǎo)致最嚴(yán)重的臨床表型[20].導(dǎo)致PLA2G6相關(guān)性肌張力障礙?帕金森綜合征的PLA2G6基因突變不影響酶活性,但改變蛋白質(zhì)之間相互作用[34].既往認(rèn)為,PLA2G6基因是帕金森病致病基因PARK14,且阿爾茨海默病患者腦組織PLA2G6蛋白水平降低[35].因此,磷脂酶A2相關(guān)性神經(jīng)變性病發(fā)病機(jī)制可能與線粒體功能障礙、脂質(zhì)代謝障礙和tau蛋白病理改變均有關(guān).

四、線粒體膜蛋白相關(guān)性神經(jīng)變性病

線粒體膜蛋白相關(guān)性神經(jīng)變性病(MPAN,OMIM編號(hào):614297)系C19orf12基因突變所致,是第3位臨床常見亞型[36],呈常染色體隱性遺傳,占所有腦組織鐵沉積性神經(jīng)變性的6%～10%[37].C19orf12蛋白是位于線粒體外膜的功能未知的蛋白質(zhì),C19orf12基因突變除可以導(dǎo)致線粒體膜蛋白相關(guān)性神經(jīng)變性病外,還與蒼白球?錐體綜合征[38]、遺傳性痙攣性截癱43型(SPG43型)[39]和肌萎縮側(cè)索硬化癥(ALS)[36]有關(guān).常見突變類型有移碼突變p.Gly69ArgfsX10和錯(cuò)義突變p.Thr11Met.通常于兒童期發(fā)病,也可于成年早期發(fā)病,兒童期發(fā)病首發(fā)癥狀為錐體束受累導(dǎo)致的痙攣步態(tài),而認(rèn)知功能障礙、構(gòu)音障礙、視神經(jīng)萎縮、錐體外系癥狀、精神行為異常、上下運(yùn)動(dòng)神經(jīng)元受累為常見臨床表現(xiàn);成年早期發(fā)病主要表現(xiàn)為帕金森樣癥狀、混合步態(tài)障礙、認(rèn)知功能障礙、精神行為異常.幾乎所有線粒體膜蛋白相關(guān)性神經(jīng)變性病患者均存在認(rèn)知功能障礙,最終進(jìn)展為癡呆,伴神經(jīng)精神異常.病變主要累及蒼白球和黑質(zhì),亦可見大腦皮質(zhì)和小腦萎縮.神經(jīng)病理學(xué)研究顯示,基底節(jié)區(qū)、新舊大腦皮質(zhì)和脊髓束均可見鐵沉積、病理性球狀軸突、tau蛋白和路易小體(LB)[37].C19orf12蛋白是包含2個(gè)替代起始密碼子的跨膜蛋白,表達(dá)于內(nèi)質(zhì)網(wǎng)和線粒體[39],導(dǎo)致SPG43型或線粒體膜蛋白相關(guān)性神經(jīng)變性病的基因突變可以改變蛋白質(zhì)分布、錯(cuò)誤蛋白質(zhì)折疊或酶活性降低.C19orf12蛋白在神經(jīng)元、白細(xì)胞和脂肪細(xì)胞中呈高表達(dá)[40].細(xì)胞模型研究顯示,白細(xì)胞體外分化期間,C19orf12蛋白水平與脂肪酸代謝密切相關(guān)[41],推測該蛋白功能與輔酶A代謝相關(guān),表明線粒體膜蛋白相關(guān)性神經(jīng)變性病與輔酶A合成酶相關(guān)性神經(jīng)變性病和磷脂酶A2相關(guān)性神經(jīng)變性病的發(fā)病機(jī)制有相似之處.

五、脂肪酸羥化酶相關(guān)性神經(jīng)變性病

FA2H基因突變與腦白質(zhì)營養(yǎng)不良、遺傳性痙攣性截癱35型(SPG35型)和腦組織鐵沉積性神經(jīng)變性病均有關(guān)[42?44],統(tǒng)稱為脂肪酸羥化酶相關(guān)性神經(jīng)變性病(FAHN,OMIM編號(hào):611026)[42],呈常染色體隱性遺傳.通常于兒童期發(fā)病,首發(fā)癥狀為步態(tài)異常、易跌倒,逐漸進(jìn)展為痙攣性步態(tài)、肌張力障礙、小腦共濟(jì)失調(diào)、構(gòu)音障礙、吞咽障礙、視神經(jīng)萎縮致視力障礙.大多數(shù)患者存在不同程度認(rèn)知功能障礙,可伴癲發(fā)作,部分患者頭部MRI檢查顯示鐵沉積.

FA2H蛋白是存在于內(nèi)質(zhì)網(wǎng)、相對(duì)分子質(zhì)量為43X103的膜結(jié)合蛋白[45].其羧基末端(C末端)含甾醇去飽和酶結(jié)構(gòu)域,其內(nèi)含鐵結(jié)合組氨酸序列并具有催化活性;氨基末端(N末端)含細(xì)胞色素B與血紅蛋白結(jié)合結(jié)構(gòu)域,涉及氧化還原活性和向C末端傳遞電子[46?47].FA2H蛋白主要作用是催化脂肪酸N??；溋u化.2?羥基脂肪酸是神經(jīng)酰胺前體,是髓鞘形成的關(guān)鍵成分[45].FA2H基因突變使酶活性缺失,導(dǎo)致羥化作用喪失而影響正常髓鞘形成.異常髓鞘形成可能誘發(fā)神經(jīng)元功能障礙和凋亡.FA2H基因突變還可以導(dǎo)致神經(jīng)酰胺信號(hào)轉(zhuǎn)導(dǎo)通路異常.此外,神經(jīng)酰胺還在神經(jīng)元凋亡和神經(jīng)變性過程中發(fā)揮重要作用[48].通過FA2H蛋白介導(dǎo)的髓鞘形成依靠溶酶體酸性神經(jīng)酰胺酶和過氧化物酶中的脂肪酸氧化,上述過程均與腦組織鐵沉積性神經(jīng)變性病相關(guān),故各種亞型之間存在潛在的相互聯(lián)系.業(yè)已證實(shí),具有鐵存儲(chǔ)功能的鐵蛋白與髓鞘形成相關(guān),并推測異常鐵沉積可能與髓鞘影響鐵蛋白的動(dòng)力學(xué)有關(guān)[42].軸突髓鞘形成可能是腦組織鐵沉積性神經(jīng)變性病各亞型共同的致病因素.如前所述,PANK2和COASY蛋白均參與輔酶A合成,后者具有多種生物學(xué)功能,尤其對(duì)神經(jīng)鞘脂的生成至關(guān)重要,而神經(jīng)鞘脂是髓鞘的另一個(gè)主要成分[49],因此,泛酸激酶相關(guān)性神經(jīng)變性病、輔酶A合成酶相關(guān)性神經(jīng)變性病與脂肪酸羥化酶相關(guān)性神經(jīng)變性病具有類似的發(fā)病機(jī)制,均影響髓鞘形成.值得注意的是,脂肪酸羥化酶相關(guān)性神經(jīng)變性病雖與髓鞘形成有關(guān),但通常不累及周圍神經(jīng)系統(tǒng).

六、β?螺旋蛋白相關(guān)性神經(jīng)變性病

WDR45基因突變可以導(dǎo)致β?螺旋蛋白相關(guān)性神經(jīng)變性病(BPAN,OMIM編號(hào):300526)[50],亦稱為兒童期靜態(tài)性腦病成年期神經(jīng)變性(SENDA),具有特征性雙相病程,即兒童期出現(xiàn)全面性發(fā)育遲滯,包括運(yùn)動(dòng)功能、言語功能和認(rèn)知功能;成年早期出現(xiàn)進(jìn)行性加重的肌張力障礙、帕金森樣癥狀和癡呆,亦可見錐體束受累.有1/4患者表現(xiàn)為兒童期智力下降和成年早期(<40歲)帕金森樣癥狀[51].頭部MRI顯示,疾病早期鐵沉積主要位于黑質(zhì),至晚期逐漸累及蒼白球[52],與其他腦組織鐵沉積性神經(jīng)變性病亞型有所不同.

WDR45蛋白(亦稱WIPI4蛋白)是一種在自噬過程中發(fā)揮作用的β?螺旋支架蛋白,是WD40蛋白家族成員,主要為蛋白質(zhì)之間的相互作用提供基礎(chǔ),并發(fā)揮如自噬、控制細(xì)胞周期和轉(zhuǎn)錄等功能.WDR45基因可以與磷脂和自噬相關(guān)蛋白結(jié)合[53],是自噬相關(guān)基因之一,對(duì)自噬體形成至關(guān)重要[54].有研究顯示,WDR45基因可以調(diào)節(jié)自噬體大小和成熟度[54].由于自噬相關(guān)基因存在于線粒體外膜,提示W(wǎng)DR45蛋白自噬體與線粒體功能之間可能存在一定聯(lián)系[55].

盡管WDR45基因定位于X染色體,但β?螺旋蛋白相關(guān)性神經(jīng)變性病并不遵循常見的X?連鎖顯性遺傳方式.在已報(bào)道的病例中,男性和女性患者均為散發(fā),且臨床特征相似,推測WDR45基因突變導(dǎo)致無功能性蛋白質(zhì),且該蛋白質(zhì)對(duì)男性胚胎具有致死性作用,男性患者基因突變多為新生突變且存在體細(xì)胞或生殖細(xì)胞嵌合現(xiàn)象,而女性患者基因突變可能與野生型X染色體失活有關(guān)[56].

由于WDR45基因與自噬有關(guān),而帕金森病、Crohn病、痙攣性截癱和腫瘤的發(fā)病機(jī)制同樣存在自噬障礙,考慮β?螺旋蛋白相關(guān)性神經(jīng)變性病的主要病變部位和病理學(xué)特征,推測其與帕金森病可能具有類似的發(fā)病機(jī)制.

七、Kufor?Rakeb 病

Kufor?Rakeb病(KRD,OMIM 編號(hào):606693)[57],亦稱PARK9相關(guān)性帕金森綜合征[58],系A(chǔ)TP13A2基因突變所致,呈常染色體隱性遺傳.通常于青少年期發(fā)病,主要表現(xiàn)為多巴反應(yīng)性帕金森綜合征、錐體束征,伴眼球運(yùn)動(dòng)障礙(核上性凝視麻痹、動(dòng)眼危象)、認(rèn)知功能障礙、神經(jīng)精神癥狀,部分表現(xiàn)為面部?咽喉?手指輕度肌陣攣和幻視.

ATP13A2蛋白是二價(jià)陽離子轉(zhuǎn)運(yùn)蛋白的溶酶體P型ATP.P型ATP是轉(zhuǎn)運(yùn)蛋白超家族成員,包括鈣泵、質(zhì)子泵和磷脂翻轉(zhuǎn)酶,由高度保守的10次跨膜蛋白組成,通過ATP跨膜轉(zhuǎn)運(yùn)離子[59].ATP13A2蛋白與溶酶體膜、線粒體和突觸膜相關(guān),其表達(dá)下調(diào)可以影響自噬體大小和數(shù)目[60].研究顯示,ATP13A2基因過表達(dá)可以抵御潛在的細(xì)胞毒性環(huán)境,如α?突觸核蛋白(α?Syn)過表達(dá)[61]和重金屬離子(鎘、錳、鎳、硒等)[62].ATP13A2基因突變患者纖維母細(xì)胞表現(xiàn)出溶酶體缺陷,在α?Syn和鋅離子[63?64]存在的情況下出現(xiàn)細(xì)胞毒性作用.與野生型細(xì)胞相比,ATP13A2基因突變細(xì)胞錳離子水平較高,提示基因突變使細(xì)胞外分泌能力下降[61],可能直接導(dǎo)致細(xì)胞色素C從線粒體釋放或細(xì)胞凋亡.在基因突變的細(xì)胞中可見細(xì)胞內(nèi)重金屬離子沉積與片段化線粒體有關(guān)[60,65].Kufor?Rakeb病患者纖維母細(xì)胞和嗅神經(jīng)元存在片段化線粒體,ATP生成減少,出現(xiàn)氧化應(yīng)激反應(yīng)和線粒體DNA損傷[66].有趣的是,ATP13A2基因缺陷細(xì)胞中并無鐵代謝失調(diào),因此,Kufor?Rakeb病患者如何發(fā)生殼核鐵沉積是進(jìn)一步研究的方向.肝豆?fàn)詈俗冃訹HLD,亦稱Wilson病(WD)]的致病基因ATP7B也屬P型ATP.生理?xiàng)l件下細(xì)胞質(zhì)內(nèi)銅離子水平升高,ATP7B蛋白從高爾基體轉(zhuǎn)移至溶酶體,由此將銅離子轉(zhuǎn)運(yùn)至溶酶體,富含銅離子的溶酶體經(jīng)胞吐作用分泌至細(xì)胞外[67].肝豆?fàn)詈俗冃允怯晒δ墚惓５腁TP7B蛋白引起,導(dǎo)致銅離子水平升高和氧化還原狀態(tài)改變.因此推測,ATP13A2蛋白功能缺陷可能導(dǎo)致重金屬離子非典型性細(xì)胞排泄減少.ATP13A2基因突變可能與溶酶體沉積之間存在聯(lián)系.此外,Kufor?Rakeb病患者還表現(xiàn)出癡呆和大腦皮質(zhì)萎縮,以及尾狀核和殼核鐵沉積,提示可能與額顳葉癡呆(FTD)、亨廷頓病(HD)有關(guān).與其他腦組織鐵沉積性神經(jīng)變性病亞型相似,ATP13A2蛋白同樣對(duì)線粒體存在影響.

八、神經(jīng)鐵蛋白變性病

神經(jīng)鐵蛋白變性病(NFT,OMIM編碼:606159),亦稱遺傳性鐵蛋白病,系鐵蛋白輕鏈(FTL)基因突變所致,呈常染色體顯性遺傳[68].鐵蛋白是主要貯存鐵離子的蛋白質(zhì),由重鏈和輕鏈亞基組成,重鏈具有鐵氧化酶活性,輕鏈有助于鐵蛋白結(jié)構(gòu)內(nèi)礦化.FTL基因突變可以引起蛋白穩(wěn)定性下降、親水性通道變寬[69],從而導(dǎo)致鐵離子貯存量下降.此外,多個(gè)細(xì)胞系和動(dòng)物實(shí)驗(yàn)證實(shí),神經(jīng)鐵蛋白變性病存在線粒體功能異常,且鐵沉積導(dǎo)致氧化應(yīng)激損傷[70],參與疾病發(fā)生.

最常見的突變類型是插入突變,主要發(fā)生于第4外顯子[71?72].頭部MRI顯示,基因攜帶者從兒童期即存在腦組織鐵沉積,直到40歲出現(xiàn)癥狀[73].神經(jīng)鐵蛋白變性病通常于40歲左右發(fā)病,臨床表現(xiàn)與亨廷頓病相似[71],主要表現(xiàn)為成年期出現(xiàn)的精神癥狀、舞蹈樣動(dòng)作和認(rèn)知功能障礙,亦可見肌張力障礙、共濟(jì)失調(diào)、帕金森樣癥狀和錐體束征等.亨廷頓病無錐體束受累可資鑒別.

九、血漿銅藍(lán)蛋白缺乏癥

CP基因突變可以導(dǎo)致血漿銅藍(lán)蛋白缺乏癥(ACP,OMIM編碼:604290)[74].通常于成年期發(fā)病,主要表現(xiàn)為糖尿病合并視網(wǎng)膜病變和成年期(25～60歲)出現(xiàn)的神經(jīng)系統(tǒng)癥狀[75],如認(rèn)知功能障礙、面部和頸部肌張力障礙、構(gòu)音障礙、震顫、舞蹈樣動(dòng)作和共濟(jì)失調(diào)等[76].約70%患者以糖尿病為首發(fā)癥狀,常合并貧血.患者血清鐵和血清銅水平較低,血清鐵蛋白水平明顯升高,達(dá)正常參考值3～40倍[77].

CP基因編碼銅藍(lán)蛋白,在中樞神經(jīng)系統(tǒng)中,銅藍(lán)蛋白主要以與糖基磷脂酰肌醇相結(jié)合的方式存在于星形膠質(zhì)細(xì)胞內(nèi)[78],病理狀態(tài)下可在星形膠質(zhì)細(xì)胞中大量聚集.目前已發(fā)現(xiàn)超過40種致病性突變[79].與其他腦組織鐵沉積性神經(jīng)變性病亞型不同,血漿銅藍(lán)蛋白缺乏癥除腦組織異常鐵沉積外,還有全身臟器的異常鐵沉積.

十、Woodhouse?Sakati綜合征

Woodhouse?Sakati綜合征(WSS,OMIM 編號(hào):241080)系DCAF17基因(曾稱C2orf37基因)突變所致,呈常染色體隱性遺傳.通常于青春期發(fā)病,主要表現(xiàn)為性功能障礙、脫發(fā)、糖尿病、智力發(fā)育遲滯、聽力障礙[80],以及錐體外系癥狀、肌張力障礙、構(gòu)音障礙和認(rèn)知功能障礙等神經(jīng)系統(tǒng)癥狀[81].部分女性患者首發(fā)癥狀為閉經(jīng)和性發(fā)育障礙,亦可見黃體生成素(LH)和卵泡刺激素(FSH)水平升高;男性患者均出現(xiàn)非梗阻性無精子癥[80].眉毛脫落和脫發(fā)程度不一,部分患者表現(xiàn)為發(fā)質(zhì)粗糙.老年患者脫發(fā)最為嚴(yán)重.所有患者均出現(xiàn)糖尿病,血清胰島素水平降低.智力障礙程度不盡一致.部分患者可出現(xiàn)聽力喪失,心電圖顯示T波低平.

DCAF17蛋白是一種多通道跨膜蛋白.動(dòng)物模型顯示,Woodhouse?Sakati綜合征小鼠腦、肝、皮膚和雄鼠生精小管中均可見DCAF17蛋白高表達(dá)[74],但其具體功能尚不明確.相關(guān)臨床研究顯示,DCAF17蛋白與參與DNA損傷和細(xì)胞周期控制的蛋白泛素化有關(guān)[82].臨床表型和蛋白表達(dá)均提示W(wǎng)oodhouse?Sakati綜合征與RBM28基因突變引起的核糖體合成缺陷相似[83],后者表現(xiàn)為垂體功能障礙,從而影響下丘腦?垂體?腎上腺(HPA)軸[75].

綜上所述,盡管腦組織鐵沉積性神經(jīng)變性病的10種亞型由10種致病基因所致,但在發(fā)病機(jī)制上相互重疊,線粒體功能障礙、氧化應(yīng)激損傷、脂質(zhì)代謝障礙、鐵沉積和自噬障礙存在于多種亞型中.腦組織異常鐵沉積究竟是腦組織鐵沉積性神經(jīng)變性病的原因還是結(jié)果,目前尚不明確.腦組織鐵沉積不僅見于腦組織鐵沉積性神經(jīng)變性,亦見于其他多種神經(jīng)變性病如阿爾茨海默病、帕金森病、亨廷頓病.腦組織鐵沉積可以引起氧化應(yīng)激反應(yīng),從而產(chǎn)生神經(jīng)毒性作用.在所有腦組織鐵沉積性神經(jīng)變性病亞型中,僅CP和FTL基因直接參與鐵代謝,而其他幾種致病基因與鐵穩(wěn)態(tài)的維持可能無直接關(guān)系.研究顯示,鐵螯合劑可以減少泛酸激酶相關(guān)性神經(jīng)變性病患者腦組織鐵沉積,但對(duì)臨床癥狀的改善并不明顯[84],因此推測腦組織鐵沉積并非導(dǎo)致臨床癥狀的主要原因.目前認(rèn)為,腦組織鐵沉積并不直接與疾病相關(guān)聯(lián),鐵代謝異?？赡芤鹌渌饘匐x子(如銅或鋅)穩(wěn)態(tài)異常,進(jìn)而導(dǎo)致神經(jīng)變性病.腦組織鐵沉積性神經(jīng)變性病與其他神經(jīng)變性病如帕金森病、額顳葉癡呆、肌萎縮側(cè)索硬化癥之間的相互聯(lián)系,既有病理學(xué)依據(jù),如tau蛋白和α?Syn,也有共同的臨床表現(xiàn)和鐵穩(wěn)態(tài)異常.因此,這些潛在的相互關(guān)聯(lián)的發(fā)病機(jī)制也可能是今后研究的方向.

[1]Schneider SA. Neurodegenerations with brain iron accumulation.Curr Neurol Neurosci Rep,2016,16:9.

[2]Zhou B,Westaway SK,Levinson B,Johnson MA,Gitschier J,Hayflick SJ.A novel pantothenate kinase gene(PANK2)is defective in Hallervorden?Spatz syndrome.Nat Genet,2001,28:345?349.

[3]Leonardi R,Rock CO,Jackowski S,Zhang YM.Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitine.Proc Natl Acad Sci USA,2007,104:1494?1499.

[4]Campanella A,Privitera D,Guaraldo M,Rovelli E,Barzaghi C,Garavaglia B,Santambrogio P,Cozzi A,Levi S.Skin fibroblasts from pantothenate kinase?associated neurodegeneration patients show altered cellular oxidative status and have defective iron?handling properties.Hum Mol Genet,2012,21:4049?4059.

[5]Chen H,Chan DC.Mitochondrial dynamics:fusion,fission,movement,and mitophagy in neurodegenerative diseases.Hum Mol Genet,2009,18:169?176.

[6]Leoni V,Strittmatter L,Zorzi G,Zibordi F,Dusi S,Garavaglia B,Venco P,Caccia C,Souza AL,Deik A,Clish CB,Rimoldi M,Ciusani E,Bertini E,Nardocci N,Mootha VK,Tiranti V.Metabolic consequences of mitochondrial coenzyme A deficiency in patients with PANK2 mutations.MolGenet Metab,2012,105:463?471.

[7]Hartig MB,H?rtnagel K,Garavaglia B,Zorzi G,Kmiec T,Klopstock T,Rostasy K,Svetel M,Kostic VS,Schuelke M,Botz E,Weindl A,Novakovic I,Nardocci N,Prokisch H,Meitinger T.Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation.Ann Neurol,2006,59:248?256.

[8]Hayflick SJ,Westaway SK,Levinson B,Zhou B,Johnson MA,Ching KH,GitschierJ.Genetic,clinical,and radiographic delineation of Hallervorden?Spatz syndrome.N Engl J Med,2003,348:33?40.

[9]Aggarwal A,Schneider SA,Houlden H,Silverdale M,Paudel R,Paisan?Ruiz C,Desai S,Munshi M,Sanghvi D,Hardy J,Bhatia KP,BhattM.Indian?subcontinentNBIA:unusual phenotypes,novel PANK2 mutations,and undetermined genetic forms.Mov Disord,2010,25:1424?1431.

[10]Hayflick SJ.Neurodegeneration with brain iron accumulation:from genes to pathogenesis.Semin Pediatr Neurol,2006,13:182?185.

[11]Marelli C,Piacentini S,Garavaglia B,Girotti F,Albanese A.Clinical and neuropsychological correlates in two brothers with pantothenate kinase?associated neurodegeneration.Mov Disord,2005,20:208?212.

[12]Thomas M,Hayflick SJ,Jankovic J.Clinical heterogeneity of neurodegeneration with brain iron accumulation(Hallervorden?Spatz syndrome) and pantothenate kinase?associated neurodegeneration.Mov Disord,2004,19:36?42.

[13]Gregory A,PolsterBJ,Hayflick SJ.Clinicaland genetic delineation of neurodegeneration with brain iron accumulation.J Med Genet,2009,46:73?80.

[14]Lee JH,Park J,Ryu HS,Park H,Kim YE,Hong JY,Nam SO,Sung YH,Lee SH,Lee JY,Lee MJ,Kim TH,Lyoo CH,Chung SJ,Koh SB,Lee PH,Cho JW,Park MY,Kim YJ,Sohn YH,Jeon BS, Lee MS. Clinical heterogeneity of atypical pantothenate kinase?associated neurodegeneration in Koreans.J Mov Disord,2016,9:20?27.

[15]Dusi S,Valletta L,Haack TB,Tsuchiya Y,Venco P,Pasqualato S,Goffrini P,Tigano M,Demchenko N,Wieland T,Chwarzmayr T,Strom TM,Invernizzi F,Garavaglia B,Gregory A,Sanford L,Hamada J,Bettencourt C,Houlden H,Chiapparini L,Zorzi G,Kurian MA,Nardocci N,Prokisch H,Hayflick S,Gout I,Tiranti V.Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation.Am J Hum Genet,2014,94:11?22.

[16]Daugherty M,Polanuyer B,Farrell M,Scholle M,Lykidis A,de Crecy?Lagard V,Osterman A.Complete reconstitution of the human coenzyme a biosynthetic pathway via comparative genomics.J Biol Chem,2002,277:21431?21439.

[17]Aghajanian S,Worrall DM.Identification and characterization of the gene encoding the human phosphopantetheine adenylyltransferase and dephospho?CoA kinasebifunctional enzyme(CoA synthase).Biochem J,2002,365:13?18.

[18]Nemazanyy I,Panasyuk G,Breus O,Zhyvoloup A,Filonenko V,Gout IT.Identification of a novel CoA synthase isoform,which is primarily expressed in thebrain.Biochem BiophysRes Commun,2006,341:995?1000.

[19]Kurian MA,Morgan NV,MacPherson L,Foster K,Peake D,Gupta R,Philip SG,Hendriksz C,Morton JE,Kingston HM,Rosser EM,Wassmer E,Gissen P,Maher ER.Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene(PLAN).Neurology,2008,70:1623?1629.

[20]Gregory A,Westaway SK,Holm IE,Kotzbauer PT,Hogarth P,Sonek S,CoryellJC,Nguyen TM,NardocciN,ZorziG,Rodriguez D,Desguerre I,Bertini E,Simonati A,Levinson B,Dias C,Barbot C,Carrilho I,Santos M,Malik I,Gitschier J,Hayflick SJ.Neurodegeneration associated with genetic defects in phospholipase A(2).Neurology,2008,71:1402?1409.

[21]Schneider SA,Dusek P,Hardy J,Westenberger A,Jankovic J,Bhatia KP.Genetics and pathophysiology of neurodegeneration with brain iron accumulation (NBIA).Curr Neuropharmacol,2013,11:59?79.

[22]Balsinde J,Balboa MA.Cellularregulation and proposed biologicalfunctions of group VIA calcium?independent phospholipase A2 in activated cells.Cell Signal,2005,17:1052?1062.

[23]Yang HC,Mosior M,Johnson CA,Chen Y,Dennis EA.Group?specific assays that distinguish between the four major types of mammalian phospholipase A2.Anal Biochem,1999,269:278?288.

[24]Song H,Bao S,Lei X,Jin C,Zhang S,Turk J,Ramanadham S.Evidence for proteolytic processing and stimulated organelle redistribution ofiPLA(2)beta.Biochim BiophysActa,2010,1801:547?558.

[25]Liou JY,Aleksic N,Chen SF,Han TJ,Shyue SK,Wu KK.Mitochondrial localization of cyclooxygenase?2 and calcium ?independent phospholipase A2 in human cancer cells:implication in apoptosis resistance.Exp Cell Res,2005,306:75?84.

[26]Seleznev K,Zhao C,Zhang XH,Song K,Ma ZA.Calcium?independent phospholipase A2 localizes in and protects mitochondria during apoptotic induction by staurosporine.J Biol Chem,2006,281:22275?22288.

[27]Ong WY,Yeo JF,Ling SF,Farooqui AA.Distribution of calcium?independent phospholipase A2 (iPLA2)in monkey brain.J Neurocytol,2005,34:447?458.

[28]Balboa MA,Balsinde J.Involvement of calcium?independent phospholipase A2 in hydrogen peroxide?induced accumulation of free fatty acids in human U937 cells.J Biol Chem,2002,277:40384?40389.

[29]Broekemeier KM,Iben JR,LeVan EG,Crouser ED,Pfeiffer DR.Pore formation and uncoupling initiate a Ca2+?independent degradation of mitochondrial phospholipids.Biochemistry,2002,41:7771?7780.

[30]Gadd ME,Broekemeier KM,Crouser ED,Kumar J,Graff G,Pfeiffer DR.Mitochondrial iPLA2 activity modulates the release of cytochrome c from mitochondria and influences the permeability transition.J Biol Chem,2006,281:6931?6939.

[31]Beck G,Sugiura Y,Shinzawa K,Kato S,Setou M,Tsujimoto Y,Sakoda S,Sumi?Akamaru H.Neuroaxonal dystrophy in calcium?independentphospholipase A2 beta deficiency resultsfrom insufficient remodeling and degeneration of mitochondrial and presynaptic membranes.J Neurosci,2011,31:11411?11420.

[32]Roy S,Zhang B,Lee VM,Trojanowski JQ.Axonal transport defects:a common theme in neurodegenerative diseases.Acta Neuropathol,2005,109:5?13.

[33]Morgan NV,Westaway SK,Morton JE,Gregory A,Gissen P,Sonek S,Cangul H,Coryell J,Canham N,Nardocci N,Zorzi G,Pasha S,Rodriguez D,Desguerre I,Mubaidin A,Bertini E,Trembath RC,Simonati A,Schanen C,Johnson CA,Levinson B,Woods CG,Wilmot B,Kramer P,Gitschier J,Maher ER,Hayflick SJ.PLA2G6,encoding a phospholipase A2,is mutated in neurodegenerative disorders with high brain iron.Nat Genet,2006,38:752?754.

[34]Engel LA,Jing Z,O'Brien DE,Sun M,Kotzbauer PT.Catalytic function of PLA2G6 is impaired by mutations associated with infantile neuroaxonal dystrophy but not dystonia?parkinsonism.PLoS One,2010,5:E12897.

[35]Ross BM,Moszczynska A,Erlich J,Kish SJ.Phospholipid?metabolizing enzymes in Alzheimer's disease: increased lysophospholipid acyltransferase activity and decreased phospholipase A2 activity.J Neurochem,2002,70:786?793.

[36]Deschauer M,Gaul C,Behrmann C,Prokisch H,Zierz S,Haack TB.C19orf12 mutations in neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis.J Neurol,2012,259:2434?2439.

[37]Arber CE,Li A,Houlden H,Wray S.Review:insights into molecular mechanisms of disease in neurodegeneration with brain iron accumulation.unifying theories.Neuropathol Appl Neurobiol,2016,42:220?241.

[38]Kruer MC,Salih MA,Mooney C,Alzahrani J,Elmalik SA,Kabiraj MM,Khan AO,Paudel R,Houlden H,Azzedine H,Alkuraya F.C19orf12 mutation leads to a pallido?pyramidal syndrome.Gene,2014,537:352?356.

[39]Landouré G,Zhu PP,Louren?o CM,Johnson JO,Toro C,Bricceno KV,Rinaldi C,Meilleur KG,Sangaré M,Diallo O,Pierson TM,Ishiura H,Tsuji S,Hein N,Fink JK,Stoll M,Nicholson G,Gonzalez MA,Speziani F,Dürr A,Stevanin G,Biesecker LG;NIH Intramural Sequencing Center;Accardi J,Landis DM,Gahl WA,Traynor BJ,Marques W Jr,Züchner S,Blackstone C,Fischbeck KH,Burnett BG.Hereditary spastic paraplegia type 43(SPG43)is caused by mutation in C19orf12.Hum Mutat,2013,34:1357?1360.

[40]Iuso A,Sibon OC,Gorza M,Heim K,Organisti C,Meitinger T,Prokisch H.Impairment of drosophila orthologs of the human orphan protein C19orf12 induces bang sensitivity and neurodegeneration.PLoS One,2014,9:E89439.

[41]Hartig MB,Iuso A,Haack T,Kmiec T,Jurkiewicz E,Heim K,Roeber S,Tarabin V,Dusi S,Krajewska?Walasek M,Jozwiak S,Hempel M,Winkelmann J,Elstner M,Oexle K,Klopstock T,Mueller?FelberW,GasserT,TrenkwalderC,TirantiV,Kretzschmar H,Schmitz G,Strom TM,Meitinger T,Prokisch H.Absence of an orphan mitochondrial protein,c19orf12,causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.Am J Hum Genet,2011,89:543?550.

[42]Kruer MC,Paisán ?Ruiz C,Boddaert N,Yoon MY,Hama H,Gregory A,Malandrini A,Woltjer RL,Munnich A,Gobin S,Polster BJ,Palmeri S,Edvardson S,Hardy J,Houlden H,Hayflick SJ.Defective FA2H leads to a novelform of neurodegeneration with brain iron accumulation(NBIA).Ann Neurol,2010,68:611?618.

[43]Edvardson S,Hama H,Shaag A,Gomori JM,Berger I,Soffer D,Korman SH,Taustein I,Saada A,Elpeleg O.Mutations in the fatty acid 2?hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia.Am J Hum Genet,2008,83:643?648.

[44]Dick KJ,Eckhardt M,Paisán?Ruiz C,Alshehhi AA,Proukakis C,Sibtain NA,Maier H,Sharifi R,Patton MA,Bashir W,Koul R,Raeburn S,Gieselmann V,Houlden H,Crosby AH.Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia(SPG35).Hum Mutat,2010,31:E1251?1260.

[45]Eckhardt M,Yaghootfam A,Fewou SN,Zoller I,Gieselmann V.A mammalian fatty acid hydroxylase responsible for the formation of alpha?hydroxylated galactosylceramide in myelin.Biochem J,2005,388:245?254.

[46]Alderson NL,Rembiesa BM,Walla MD,Bielawska A,Bielawski J,Hama H.The human FA2H gene encodes a fatty acid 2?hydroxylase.J Biol Chem,2004,279:48562?48568.

[47]Hama H.Fatty acid 2?hydroxylation in mammalian sphingolipid biology.Biochim Biophys Acta,2010,1801:405?414.

[48]Jana A,Hogan EL,Pahan K.Ceramide and neurodegeneration:susceptibility of neurons and oligodendrocytes to cell damage and death.J Neurol Sci,2009,278:5?15.

[49]Liman J,Wellmer A,Rostasy K,BahrM,Kermer P.Transcranial ultrasound in neurodegeneration with brain iron accumulation(NBIA).Eur J Paediatr Neurol,2012,16:175?178.

[50]Doorn JM, Kruer MC. Newly characterized forms of neurodegeneration with brain iron accumulation.Curr Neurol Neurosci Rep,2013,13:413.

[51]NishiokaK,OyamaG,YoshinoH,LiY,MatsushimaT,Takeuchi C,Mochizuki Y,Mori?Yoshimura M,Murata M,Yamasita C,Nakamura N,Konishi Y,Ohi K,Ichikawa K,Terada T,Obi T,FunayamaM,Saiki S,Hattori N.High frequency of beta?propeller protein?associated neurodegeneration (BPAN)among patients with intellectual disability and young?onsetparkinsonism.NeurobiolAging,2015,36:2004.

[52]Hayflick SJ,Kruer MC,Gregory A,Haack TB,Kurian MA,Houlden HH,Anderson J,Boddaert N,Sanford L,Harik SI,Dandu VH,Nardocci N,Zorzi G,Dunaway T,Tarnopolsky M,SkinnerS,Holden KR,FruchtS,HanspalE,Schrander?Stumpel C,Mignot C,Héron D,Saunders DE,Kaminska M,Lin JP,Lascelles K,Cuno SM,Meyer E,Garavaglia B,Bhatia K,de Silva R,Crisp S,Lunt P,Carey M,Hardy J,Meitinger T,Prokisch H,Hogarth P.β ?Propellerprotein?associated neurodegeneration:a new X?linked dominant disorder with brain iron accumulation.Brain,2013,136:1708?1717.

[53]Lu Q,Yang P,Huang X,Hu W,Guo B,Wu F,Lin L,Kovacs AL,Yu L,Zhang H.The WD40 repeat PtdIns(3)P?binding protein EPG?6 regulates progression ofomegasomes to autophagosomes.Dev Cell,2011,21:343?357.

[54]Dall'Armi C,Devereaux KA,Di Paolo G.The role of lipids in the control of autophagy.Curr Biol,2013,23:33?45.

[55]Hailey DW,Rambold AS,Satpute?Krishnan P,Mitra K,Sougrat R,Kim PK,Lippincott?Schwartz J.Mitochondria supply membranes forautophagosome biogenesis during starvation.Cell,2010,141:656?667.

[56]Haack TB,Hogarth P,Kruer MC,Gregory A,Wieland T,Schwarzmayr T,Graf E,Sanford L,Meyer E,Kara E,Cuno SM,Harik SI,Dandu VH,NardocciN,ZorziG,DunawayT,Tarnopolsky M,Skinner S,Frucht S,Hanspal E,Schrander?Stumpel C,Héron D,Mignot C,Garavaglia B,Bhatia K,Hardy J,Strom TM,Boddaert N,Houlden HH,Kurian MA,Meitinger T,Prokisch H,Hayflick SJ.Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct,X?linked dominant form of NBIA.Am J Hum Genet,2012,91:1144?1149.

[57]Najim al?Din AS,al?Kurdi A,Dasouki M,Wriekat AL,al?Khateeb M,Mubaidin A,al?Hiari M.Autosomal recessive ataxia,slow eyemovements and psychomotor retardation.J Neurol Sci,1994,124:61?66.

[58]Di Fonzo A,Chien HF,Socal M,Giraudo S,Tassorelli C,Iliceto G,Fabbrini G,Marconi R,Fincati E,Abbruzzese G,Marini P,Squitieri F,Horstink MW,Montagna P,Libera AD,Stocchi F,Goldwurm S,Ferreira JJ,Meco G,Martignoni E,Lopiano L,Jardim LB,Oostra BA,Barbosa ER;Italian Parkinson Genetics Network;Bonifati V.ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease.Neurology,2007,68:1557?1562.

[59]Kühlbrandt W.Biology,structure and mechanism of P ?type ATPases.Nat Rev Mol Cell Biol,2004,5:282?295.

[60]Ramonet D,Podhajska A,Stafa K,Sonnay S,Trancikova A,Tsika E,Pletnikova O,Troncoso JC,Glauser L,Moore DJ.PARK9?associated ATP13A2 localizes to intracellular acidic vesicles and regulates cation homeostasis and neuronal integrity.Hum Mol Genet,2012,21:1725?1743.

[61]Tan J,Zhang T,Jiang L,Chi J,Hu D,Pan Q,Wang D,Zhang Z.Regulation of intracellular manganese homeostasis by Kufor?Rakeb syndrome?associated ATP13A2 protein.J Biol Chem,2011,286:29654?29662.

[62]Schmidt K,Wolfe DM,Stiller B,Pearce DA.Cd2+,Mn2+,Ni2+and Se2+toxicity to saccharomyces cerevisiae lacking YPK9p the orthologue of human ATP13A2.Biochem Biophys Res Commun,2009,383:198?202.

[63]UsenovicM,Tresse E,Mazzulli JR,Taylor JP,Krainc D.Deficiency of ATP13A2 leads to lysosomal dysfunction,alpha?synuclein accumulation,and neurotoxicity.J Neurosci,2012,32:4240?4246.

[64]Tsunemi T,Krainc D.Zn2+dyshomeostasis caused by loss of ATP13A2/PARK9 leads to lysosomal dysfunction and alpha?synuclein accumulation.Hum Mol Genet,2014,23:2791?2801.

[65]Park JS,Koentjoro B,Veivers D,Mackay?Sim A,Sue CM.Parkinson'sdisease?associated human ATP13A2 (PARK9)deficiency causes zinc dyshomeostasis and mitochondrial dysfunction.Hum Mol Genet,2014,23:2802?2815.

[66]Grunewald A,Arns B,Seibler P,Rakovic A,Munchau A,Ramirez A,Sue CM,KleinC.ATP13A2mutations impair mitochondrial function in fibroblasts from patients with Kufor?Rakeb syndrome.Neurobiol Aging,2012,33:1843.

[67]Polishchuk EV,Concilli M,Iacobacci S,Chesi G,Pastore N,Piccolo P,Paladino S,Baldantoni D,van IJzendoorn SC,Chan J,Chang CJ,Amoresano A,Pane F,Pucci P,Tarallo A,Parenti G,Brunetti?Pierri N,Settembre C,Ballabio A,Polishchuk RS.Wilson disease protein ATP7B utilizes lysosomal exocytosis to maintain copper homeostasis.Developmental Cell,2014,29:686?700.

[68]Curtis AR,Fey C,Morris CM,Bindoff LA,Ince PG,Chinnery PF,Coulthard A,Jackson MJ,Jackson AP,McHale DP,Hay D,Barker WA,Markham AF,Bates D,Curtis A,Burn J.Mutation in the gene encoding ferritin light polypeptide causes dominant adult?onset basal ganglia disease.Nat Genet,2001,28:350?354.

[69]Colombelli C,Aoun M,Tiranti V.Defective lipid metabolism in neurodegeneration with brain iron accumulation (NBIA)syndromes:not only a matter of iron.J Inherit Metab Dis,2015,38:123?136.

[70]Mancuso M,Davidzon G,Kurlan RM,Tawil R,Bonilla E,Di Mauro S, Powers JM. Hereditary ferritinopathy: a novel mutation,its cellular pathology,and pathogenetic insights.J Neuropathol Exp Neurol,2005,64:280?294.

[71]Chinnery PF,Crompton DE,Birchall D,Jackson MJ,Coulthard A,Lombès A,Quinn N,Wills A,Fletcher N,Mottershead JP,Cooper P,Kellett M,Bates D,Burn J.Clinical features and naturalhistory ofneuroferritinopathy caused by the FTL1 460InsA mutation.Brain,2007,130:110?119.

[72]Chinnery PF,Curtis AR,Fey C,Coulthard A,Crompton D,Curtis A,Lombes A,Burn J.Neuroferritinopathy in a French family with late onset dominant dystonia.J Med Genet,2003,40:E69.

[73]Keogh MJ,JonasP,Coulthard A,ChinneryPF,Burn J.Neuroferritinopathy:a new inborn error of iron metabolism.Neurogenetics,2012,13:93?96.

[74]Yoshida K,Furihata K,Takeda S,Nakamura A,Yamamoto K,Morita H,Hiyamuta S,Ikeda S,Shimizu N,Yanagisawa N.A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans.Nat Genet,1995,9:267?272.

[75]Miyajima H.Aceruloplasminemia.Rinsho Shinkeigaku,2000,40:1290?1292.

[76]McNeill A,Pandolfo M,Kuhn J,Shang H,Miyajima H.The neurological presentation of ceruloplasmin gene mutations.Eur Neurol,2008,60:200?205.

[77]Ogimoto M,Anzai K,Takenoshita H,Kogawa K,Akehi Y,Yoshida R,Nakano M,Yoshida K,Ono J.Criteria for early identification of aceruloplasminemia.Intern Med,2011,50:1415?1418.

[78]Wild EJ,Mudanohwo EE,Sweeney MG,Schneider SA,Beck J,Bhatia KP,Rossor MN,Davis MB,Tabrizi SJ.Huntington's disease phenocopies are clinically and genetically heterogeneous.Mov Disord,2008,23:716?720.

[79]Crompton DE,Chinnery PF,Bates D,Walls TJ,Jackson MJ,Curtis AJ,Burn J.Spectrum ofmovement disorders in neuroferritinopathy.Mov Disord,2005,20:95?99.

[80]WoodhouseNJ,SakatiNA.A syndromeofhypogonadism,alopecia,diabetes mellitus,mental retardation,deafness,and ECG abnormalities.J Med Genet,1983,20:216?219.

[81]Al?Semari A,Bohlega S.Autosomal?recessive syndrome with alopecia,hypogonadism,progressive extra?pyramidal disorder,white matter disease,sensory neural deafness,diabetes mellitus,and low IGF1.Am J Med Genet A,2007,143A:149?160.

[82]Jin J,Arias EE,Chen J,Harper JW,Walter JC.A family of diverse Cul4?Ddb1?interacting proteins includes Cdt2,which is required for S phase destruction of the replication factor Cdt1.Mol Cell,2006,23:709?721.

[83]Nousbeck J,Spiegel R,Ishida?Yamamoto A,Indelman M,Shani?Adir A,Adir N,Lipkin E,Bercovici S,Geiger D,van Steensel MA,Steijlen PM,Bergman R,Bindereif A,Choder M,Shalev S,Sprecher E.Alopecia,neurological defects,and endocrinopathy syndrome caused by decreased expression ofRBM28,a nucleolar protein associated with ribosome biogenesis.Am J Hum Genet,2008,82:1114?1121.

[84]Zorzi G,Zibordi F,Chiapparini L,Bertini E,Russo L,Piga A,Longo F,Garavaglia B,Aquino D,Savoiardo M,Solari A,NardocciN.Iron?related MRIimages in patients with pantothenate kinase?associated neurodegeneration (PKAN)treated with deferiprone:results of a phaseⅡpilot trial.Mov Disord,2011,26:1756?1759.

Genetic research advance on neurodegeneration with brain iron accumulation

HUANG Xiao?jun1,CAO Li21Department of Neurology,North Department of Ruijin Hospital,School of Medicine,Shanghai Jiaotong University,Shanghai 201801,China
2Department of Neurology and Institute of Neurology,Ruijin Hospital,School of Medicine,Shanghai Jiaotong University,Shanghai 200025,China

CAO Li(Email:caoli2000@yeah.net)

Neurodegeneration with brain iron accumulation(NBIA)is a neurodegenerative disorder characterized by abnormal accumulation of iron in central nervous system.Common clinical symptoms in NBIA include different types of dyskinesia,pyramidal tract involvement,cerebellar ataxia,peripheral neuropathy,autonomic neuropathy,cognitive impairment and visual dysfunction.So far,10 genes have been identified as the causative gene for NBIA subtypes,which are PANK2,COASY,PLA2G6,C19orf12,FA2H,WDR45,ATP13A2,FTL,CP and DCAF17.The pathogenesis of NBIA involves mitochondrial involvement,oxidative stress damage,lipid metabolism and autophagy.Furthermore,NBIA may share the same pathogenetic mechanism with some other neurodegenerative disorders,such as Parkinson's disease(PD),frontotemporal dementia(FTD)and amyotrophic lateral sclerosis(ALS).

Neurodegenerative diseases; Iron metabolism disorders; Genetics; Review

This study was supported by the National Natural Science Foundation of China(No.81571086),the National Natural Science Foundation of China for Young Scientists(No.81600978),Shanghai Jiaotong University School of Medicine Peak and Plateau Program(No.20161401),and Crossing Program between Medicine and Industry supported by Shanghai Jiaotong University(No.YG2016MS64).

10.3969/j.issn.1672?6731.2017.07.004

國家自然科學(xué)基金資助項(xiàng)目(項(xiàng)目編號(hào):81571086);國家自然科學(xué)基金青年科學(xué)基金資助項(xiàng)目(項(xiàng)目編號(hào):81600978);上海交通大學(xué)醫(yī)學(xué)院高峰高原計(jì)劃(項(xiàng)目編號(hào):20161401);上海交通大學(xué)"醫(yī)工交叉研究基金"資助項(xiàng)目(項(xiàng)目編號(hào):YG2016MS64)

201801上海交通大學(xué)醫(yī)學(xué)院附屬瑞金醫(yī)院北院神經(jīng)內(nèi)科(黃嘯君);200025上海交通大學(xué)醫(yī)學(xué)院附屬瑞金醫(yī)院神經(jīng)科 上海交通大學(xué)醫(yī)學(xué)院神經(jīng)病學(xué)研究所(曹立)

曹立(Email:caoli2000@yeah.net)

2017?05?31)