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首页> 外文期刊>Neuroscience Research: The Official Journal of the Japan Neuroscience Society >Phosphorylated TDP-43 becomes resistant to cleavage by calpain: A regulatory role for phosphorylation in TDP-43 pathology of ALS/FTLD
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Phosphorylated TDP-43 becomes resistant to cleavage by calpain: A regulatory role for phosphorylation in TDP-43 pathology of ALS/FTLD

机译：磷酸化的TDP-43变得对钙蛋白酶的切割具有抗性：在ALS / FTLD的TDP-43病理中磷酸化的调节作用

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摘要

TAR DNA-binding protein-43 (TDP-43) pathology, which includes the presence of abnormal TDP-43-containing inclusions with a loss of nuclear TDP-43 in affected neurons, is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and/or frontotemporal lobar degeneration (FTLD). TDP-43 in the pathological brains and spinal cords of ALS/FTLD patients is abnormally fragmented and phosphorylated. It is believed that the generation of aggregation-prone TDP-43 fragments initiates TDP-43 pathology, and we previously reported that calpain has an important role in the generation of such aggregation prone TDP-43 fragments. However, the role of phosphorylation in TDP-43 pathology has not been largely elucidated, despite previous observations that several kinases and their kinases are involved in TDP-43 phosphorylation. Here, we investigated the role of TDP-43 phosphorylation in the calpain-dependent cleavage of TDP-43 and found that phosphorylated, full-length TDP-43 and calpain-dependent TDP-43 fragments were more resistant to cleavage by calpain than endogenous full-length TDP-43 was. These results suggest that both phosphorylated and calpain-cleaved TDP-43 fragments persist intracellularly for a length of time that is sufficient for self-aggregation, thereby serving as seeds for inclusions. (C ) 2015 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.
机译：TAR DNA结合蛋白43（TDP-43）病理学是肌萎缩性侧索硬化症（ALS）的病理学特征，其中包括异常TDP-43内含物的存在以及核TDP-43的丢失。 /或额颞叶变性（FTLD）。 ALS / FTLD患者的病理性脑和脊髓中的TDP-43异常断裂和磷酸化。据信易于聚集的TDP-43片段的产生引发了TDP-43的病理学，并且我们先前报道了钙蛋白酶在这种易于聚集的TDP-43片段的产生中具有重要作用。然而，尽管先前观察到几种激酶及其激酶参与TDP-43磷酸化，但尚未充分阐明磷酸化在TDP-43病理学中的作用。在这里，我们研究了TDP-43磷酸化在TDP-43的钙蛋白酶依赖性切割中的作用，发现磷酸化的全长TDP-43和钙蛋白酶依赖性的TDP-43片段比内源性完整蛋白酶更耐钙蛋白酶切割长TDP-43。这些结果表明磷酸化和钙蛋白酶切割的TDP-43片段在细胞内持续一段足以自我聚集的时间，从而成为包涵体的种子。 （C）2015爱思唯尔爱尔兰有限公司和日本神经科学协会。版权所有。

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