3月30日，美國(guó)The FASEB Journal在線發(fā)表了中科院上海生命科學(xué)研究院生化與細(xì)胞所胡紅雨課題組的研究論文,。該論文闡明了TDP-43蛋白的降解片段TDP-35是其在細(xì)胞質(zhì)內(nèi)形成包涵體的主要原因,，并且包涵體的形成引起該蛋白質(zhì)參與RNA加工功能的改變。
肌萎縮側(cè)索硬化癥(Amyotrophic Lateral Sclerosis, ALS)和額顳葉變性（Frontotemporal Lobar Degeneration,，F(xiàn)TLD)是兩類有類似臨床表征的神經(jīng)退行性疾病,，它們的主要病理特征是神經(jīng)元的退化，而存活的神經(jīng)細(xì)胞內(nèi)有大量包涵體存在,。在這兩類疾病患者神經(jīng)細(xì)胞的包涵體中發(fā)現(xiàn)有TDP-43蛋白及其C-端裂解產(chǎn)物的大量沉積,。TDP-43蛋白的N-端含有兩個(gè)串聯(lián)的RNA識(shí)別模體，而C-端為豐富甘氨酸的天然無(wú)結(jié)構(gòu)區(qū)域,。在病理情況下,，TDP-43蛋白會(huì)發(fā)生片段化，產(chǎn)生兩個(gè)C-端的降解片段,。然而,，TDP-43發(fā)生積聚的分子機(jī)制以及形成的包涵體對(duì)細(xì)胞造成的影響還不清楚。
博士生車美霞等人首先利用生物化學(xué)和細(xì)胞生物學(xué)方法研究了TDP-43片段化對(duì)包涵體形成及對(duì)細(xì)胞mRNA加工的影響,。在HEK 293T細(xì)胞株中過(guò)表達(dá)TDP-43及其C-端片段時(shí)發(fā)現(xiàn),，TDP-43蛋白定位于細(xì)胞核內(nèi)且不形成包涵體；而TDP-35在細(xì)胞質(zhì)中形成包涵體,，并且能夠?qū)DP-43蛋白招募至細(xì)胞質(zhì)包涵體中,。TDP-43蛋白參與mRNA前體的剪切,，而TDP-35則表現(xiàn)出與其相反的功能。通過(guò)對(duì)體外純化蛋白質(zhì)的研究發(fā)現(xiàn),，TDP-43蛋白雖然是一個(gè)寡聚體,，但不容易積聚形成沉淀，而TDP-35蛋白則容易積聚形成沉淀,；而且TDP-35蛋白具有種子效應(yīng),，能夠促進(jìn)TDP-43蛋白的積聚和沉淀，這可能是病理情況下TDP-43蛋白形成包涵體的一個(gè)重要因素,。
這些研究成果加深了人們對(duì)于細(xì)胞內(nèi)包涵體形成和上述兩類神經(jīng)退行性疾病病理發(fā)生過(guò)程的認(rèn)識(shí),。
該研究工作得到了國(guó)家科技部、基金委,、中國(guó)科學(xué)院的經(jīng)費(fèi)支持,。（生物谷Bioon.com）
生物谷推薦原文出處：
The FASEB Journal doi: 10.1096/fj.10-174482
Aggregation of the 35-kDa fragment of TDP-43 causes formation of cytoplasmic inclusions and alteration of RNA processing
Mei-Xia Che, Ya-Jun Jiang, Yuan-Yuan Xie, Lei-Lei Jiang and Hong-Yu Hu1
TAR DNA binding protein of 43 kDa (TDP-43) is a nuclear factor functioning in RNA processing. It is also a major deposited protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin (FTLD-U). To understand the mechanism underlying the inclusion body formation and possible functional alteration, we studied some TDP-43 fragments and their effects on RNA processing in cell models. The results show that the 35-kDa fragment of TDP-43 (namely TDP-35, residues 90–414), but not TDP-25A (184–414), is capable of forming cytoplasmic inclusion bodies and altering pre-mRNA splicing. The inclusions formed by TDP-35 can also recruit full-length TDP-43 to cytoplasmic deposition from functionally nuclear localization. The in vitro studies demonstrate that TDP-35, rather than TDP-43 and TDP-25A, is prone to aggregation, and it further serves as a seed to facilitate aggregation of full-length TDP-43. This suggests that fragmentation of TDP-43 leads to cellular redistribution, inclusion body formation, and altered RNA processing, which are implicated in the molecular pathogenesis of ALS and FTLD.—Che, M.-X., Jiang, Y.-J., Xie, Y.-Y., Jiang, L.-L., Hu, H.-Y. Aggregation of the 35-kDa fragment of TDP-43 causes formation of cytoplasmic inclusions and alteration of RNA processing.
