Analysis of RNA metabolism in peripheral WBCs of TDP-43 KI mice identifies novel biomarkers of ALS
Analysis of RNA metabolism in peripheral WBCs of TDP-43 KI mice identifies novel biomarkers of ALS
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DOI：
10.1016/j.neures.2015.11.009
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发表时间：
2016-05-01
影响因子：
2.9
通讯作者：
Okano, Hirotaka James
中科院分区：
文献类型：
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作者：
Hasegawa, Minami;Hara-Miyauchi, Chikako;Okano, Hirotaka James
肌萎缩侧索硬化症(ALS)的诊断生物标志物尚未确定。神经退行性疾病中神经细胞死亡的原因之一是RNA代谢异常，尽管发生这种情况的机制尚不清楚。检测白细胞(WBC)中的RNA代谢异常可能导致ALS发病的一个新的生物标志物。TAR DNA结合蛋白43 kDa(TDP-43)是一种调节RNA代谢的RNA结合蛋白。我们之前开发了一个表现为成人型运动功能障碍的ALS小鼠模型；这些突变的TDP-43敲入(KI)小鼠杂合表达突变的人TDP-43(A382T或G348C)。在本研究中，我们检测了Ki小鼠WBC中TDP-43的mRNA水平，发现A382T突变的mRNA显著高于G348C。我们的结果表明，每个突变体TDP-43都诱导了不同的RNA代谢，WBC中总TDP-43的单独表达不适合作为ALS的生物标志物。为了确定其他候选基因，我们将重点放在了与生存和凋亡相关的因子上，并检测了它们在WBC中的mRNA代谢。SMN1和NAIP5的mRNA水平与TDP-43水平相关，A382T和G348C之间也有差异。TDP-43和这些因子结合在一起，可能能够检测到个别ALS病理中的异常。(C)2015年提交人。爱思唯尔爱尔兰有限公司出版。
Diagnostic biomarkers for amyotrophic lateral sclerosis (ALS) have yet to be identified. One of the causes of neuronal cell death in neurodegenerative diseases is abnormal RNA metabolism, although the mechanisms by which this occurs are unclear. Detection of abnormal RNA metabolism in white blood cells (WBCs) could lead to a new biomarker of ALS onset. TAR DNA-binding protein 43 kDa (TDP-43) is an RNA-binding protein that regulates RNA metabolism. We previously developed a mouse model of ALS that exhibits adult-onset motor dysfunction; these mutant TDP-43 knock in (KI) mice heterozygously express mutant human TDP-43 (A382T or G348C). In the present study, we examined TDP-43 mRNA levels in WBCs of KI mice and found that A382T mutant mRNA is significantly higher than G348C. Our results suggest that each mutant TDP-43 induces distinct RNA metabolism, and that the expression of total TDP-43 alone in WBC is not suitable as an ALS biomarker. To identify additional candidates, we focused on survival and apoptosis-related factors and examined their mRNA metabolism in WBCs. mRNA levels of both Smn1 and Naip5 correlated with TDP-43 levels and also differed between A382T and G348C. Together, TDP-43 and these factors may enable detection of abnormalities in individual ALS pathologies. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.