3月30日，美国The FASEB Journal在线发表了中科院上海生命科学研究院生化与细胞所胡红雨课题组的研究论文。该论文阐明了TDP-43蛋白的降解片段TDP-35是其在细胞质内形成包涵体的主要原因，并且包涵体的形成引起该蛋白质参与RNA加工功能的改变。
肌萎缩侧索硬化症(Amyotrophic Lateral Sclerosis, ALS)和额颞叶变性（Frontotemporal Lobar Degeneration，FTLD)是两类有类似临床表征的神经退行性疾病，它们的主要病理特征是神经元的退化，而存活的神经细胞内有大量包涵体存在。在这两类疾病患者神经细胞的包涵体中发现有TDP-43蛋白及其C-端裂解产物的大量沉积。TDP-43蛋白的N-端含有两个串联的RNA识别模体，而C-端为丰富甘氨酸的天然无结构区域。在病理情况下，TDP-43蛋白会发生片段化，产生两个C-端的降解片段。然而，TDP-43发生积聚的分子机制以及形成的包涵体对细胞造成的影响还不清楚。
博士生车美霞等人首先利用生物化学和细胞生物学方法研究了TDP-43片段化对包涵体形成及对细胞mRNA加工的影响。在HEK 293T细胞株中过表达TDP-43及其C-端片段时发现，TDP-43蛋白定位于细胞核内且不形成包涵体；而TDP-35在细胞质中形成包涵体，并且能够将TDP-43蛋白招募至细胞质包涵体中。TDP-43蛋白参与mRNA前体的剪切，而TDP-35则表现出与其相反的功能。通过对体外纯化蛋白质的研究发现，TDP-43蛋白虽然是一个寡聚体，但不容易积聚形成沉淀，而TDP-35蛋白则容易积聚形成沉淀；而且TDP-35蛋白具有种子效应，能够促进TDP-43蛋白的积聚和沉淀，这可能是病理情况下TDP-43蛋白形成包涵体的一个重要因素。
这些研究成果加深了人们对于细胞内包涵体形成和上述两类神经退行性疾病病理发生过程的认识。
该研究工作得到了国家科技部、基金委、中国科学院的经费支持。（生物谷Bioon.com）
生物谷推荐原文出处：
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.
