Aggregation of the 35-kDa fragment of TDP-43 causes formation of cytoplasmic inclusions and alteration of RNA processing
Aggregation of the 35-kDa fragment of TDP-43 causes formation of cytoplasmic inclusions and alteration of RNA processing
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DOI：
10.1096/fj.10-174482
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发表时间：
2011-07-01
期刊：
影响因子：
4.8
通讯作者：
Hu, Hong-Yu
中科院分区：
文献类型：
--
作者：
Che, Mei-Xia;Jiang, Ya-Jun;Hu, Hong-Yu
43 kDa的TAR DNA结合蛋白（TDP-43）是参与RNA加工的核因子。它也是肌萎缩性侧索硬化症（ALS）和泛素额颞叶变性（FTLD-U）的主要沉积蛋白。为了了解包涵体形成的机制和可能的功能改变，我们在细胞模型中研究了一些TDP-43片段及其对RNA加工的影响。结果表明，TDP-43的35 kda片段（即TDP-35，残基90-414）能够形成细胞质包涵体并改变pre-mRNA剪接，而TDP-25A（184-414）则不能。TDP-35形成的包涵体也可以从功能性核定位中招募全长TDP-43到细胞质沉积。体外研究表明，TDP-35比TDP-43和TDP-25A更容易聚集，并进一步作为种子促进全长TDP-43的聚集。这表明TDP-43的断裂导致细胞重分布、包涵体形成和RNA加工的改变，这些都与ALS和FTLD的分子发病机制有关。切,M.-X。蒋，y - j。，谢，y - y。蒋丽丽。，胡，h - y。TDP-43的35kda片段聚集导致细胞质包涵体的形成和RNA加工的改变。中国生物医学工程学报，25(2):444 - 453（2011）。www.fasebj.org
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. FASEB J. 25, 2344-2353 (2011). www.fasebj.org