內(nèi)質(zhì)網(wǎng)是一種多功能的細(xì)胞器，在蛋白的分泌、折疊、質(zhì)量控制、翻譯后修飾、Ca2+存儲(chǔ)，信號(hào)傳導(dǎo)等細(xì)胞活動(dòng)中起關(guān)鍵性作用。各種病理生理因素如Ca2+耗竭、氧化應(yīng)激、通過分泌途徑分泌的突變蛋白質(zhì)等導(dǎo)致非折疊或錯(cuò)誤折疊蛋白質(zhì)在內(nèi)質(zhì)網(wǎng)腔中蓄積引起內(nèi)質(zhì)網(wǎng)應(yīng)激(endoplasmic reticulum stress, ER stress)，即內(nèi)質(zhì)網(wǎng)內(nèi)穩(wěn)態(tài)失衡。內(nèi)質(zhì)網(wǎng)為重建動(dòng)態(tài)平衡激活非折疊蛋白反應(yīng)(unfolded protein response, UPR)[1]。內(nèi)質(zhì)網(wǎng)穩(wěn)態(tài)失衡可觸發(fā)ER stress感應(yīng)器X-盒結(jié)合蛋白1(Xbox binding protein-1, XBP1)、PERK (protein kinase RNA like ER kinase)和IRE1α(inositol-requiring enzyme-1alpha)相關(guān)的適應(yīng)性信號(hào)級(jí)聯(lián)反應(yīng)。正常狀態(tài)下內(nèi)質(zhì)網(wǎng)糖調(diào)節(jié)蛋白(glucose regulated protein 78, GRP78/Bip)與UPR三條主要信號(hào)反應(yīng)通路跨膜蛋白IRE1(inositol-requiring protein-1)、ATF6(activating transcription factor-6)以及PERK結(jié)合，使其處于失活狀態(tài)， ER stress一旦發(fā)生，Bip即與未折疊蛋白結(jié)合并與這三個(gè)蛋白解離，激活這些受體蛋白胞質(zhì)表面結(jié)構(gòu)，通過增加分子伴侶鈣聯(lián)蛋白(calnexin)、蛋白二硫化物異構(gòu)酶(protein disulfide isomerase, PDI)、鈣網(wǎng)織蛋白(calreticulin)等的表達(dá)、減少全局蛋白翻譯、增加未折疊/錯(cuò)誤折疊蛋白降解并通過內(nèi)質(zhì)網(wǎng)相關(guān)的降解(ER associated degradation, ERAD)來減輕ER stress、保護(hù)細(xì)胞[2]。
阿爾茨海默病(Alzheimer's disease, AD)是一種常見的神經(jīng)退行性病變，以進(jìn)行性認(rèn)知功能障礙伴有行為、語言、視覺空間記憶記憶損傷為主要臨床癥狀，最終導(dǎo)致個(gè)體過早死亡。尸檢神經(jīng)病理學(xué)發(fā)現(xiàn)，AD病人大腦皮質(zhì)和皮質(zhì)下神經(jīng)元及突觸選擇性缺失，細(xì)胞外淀粉樣蛋白(amyloid β, Aβ)大量堆積，細(xì)胞內(nèi)含有過度磷酸化tau蛋白神經(jīng)纖維纏結(jié)(neurofibrillary tangles, NFT)并發(fā)生淀粉樣血管病變[3]。研究表明，Aβ干擾內(nèi)質(zhì)網(wǎng)功能導(dǎo)致AD患者早期即出現(xiàn)ER stress[4]。同時(shí)Aβ可引起原代神經(jīng)元出現(xiàn)ER stress進(jìn)而激活線粒體或內(nèi)質(zhì)網(wǎng)介導(dǎo)的細(xì)胞凋亡[5]。
參考文獻(xiàn)
[1] Plácido AI, Pereira CM, Duarte AI, et al. The role of endoplasmic reticulum in amyloid precursor protein processing and trafficking: implications for Alzheimer's disease [J]. Biochimica et biophysica acta, 2014, 1842(9): 1444-1453.
[2] Bernales S, Soto MM, McCullagh E. Unfolded protein stress in the endoplasmic reticulum and mitochondria: a role in neurodegeneration [J]. Frontiers in aging neuroscience, 2012, 4: 5.
[3] Querfurth HW, LaFerla FM. Alzheimer's disease [J]. The New England journal of medicine, 2010, 362(4): 329-344.
[4] Unterberger U，H?ftberger R, Gelpi, Ellen, et al. Endoplasmic reticulum stress features are prominent in Alzheimer disease but not in prion diseases in vivo [J]. Journal of neuropathology and experimental neurology, 2006, 65(4): 348-357.
[5] Costa RO, Ferreiro E, Cardoso SM, et al. ER stress-mediated apoptotic pathway induced by Abeta peptide requires the presence of functional mitochondria [J]. Journal of Alzheimer's disease : JAD, 2010, 20(2): 625-636.
（王海云）
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