Accumulation of C-terminal fragments of transactive response DNA-binding protein 43 leads to synaptic loss and cognitive deficits in human TDP-43 transgenic mice
Accumulation of C-terminal fragments of transactive response DNA-binding protein 43 leads to synaptic loss and cognitive deficits in human TDP-43 transgenic mice
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DOI：
10.1016/j.neurobiolaging.2013.07.006
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发表时间：
2014-01-01
影响因子：
4.2
通讯作者：
Oddo, Salvatore
中科院分区：
文献类型：
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作者：
Medina, David X.;Orr, Miranda E.;Oddo, Salvatore
反式反应DNA结合蛋白43（TDP-43）的积累是几种神经退行性疾病的主要标志，统称为TDP-43蛋白病。最常见的TDP-43蛋白病、额颞叶变性伴TDP-43阳性包涵体和肌萎缩侧索硬化症具有重叠的神经病理学和临床表型。TDP-43蛋白病动物模型的开发和详细分析对于理解这些疾病的发病机制至关重要。过表达突变型人TDP-43（本文称为hTDP-43）的转基因小鼠的特征在于神经变性和寿命缩短。然而，对这些小鼠的行为表型知之甚少。在这里，我们报告了新的发现，hTDP-43小鼠在认知，运动表现和协调方面出现缺陷。我们发现，这些行为缺陷与积累的核和胞质TDP-43 C-末端片段，内源性TDP-43水平下降，和突触丢失。我们的研究结果为疾病病理学提供了重要的见解，并将有助于指导未来的临床前研究，旨在测试潜在治疗药物对TDP-43蛋白病的发作和进展的影响。(C)2014爱思唯尔公司All rights reserved.
Accumulation of the transactive response DNA-binding protein 43 (TDP-43) is a major hallmark of several neurodegenerative disorders, collectively known as TDP-43 proteinopathies. The most common TDP-43 proteinopathies, frontotemporal lobar degeneration with TDP-43-positive inclusions, and amyotrophic lateral sclerosis, share overlapping neuropathological and clinical phenotypes. The development and detailed analysis of animal models of TDP-43 proteinopathies are critical for understanding the pathogenesis of these disorders. Transgenic mice overexpressing mutant human TDP-43 (herein referred to as hTDP-43) are characterized by neurodegeneration and reduced life span. However, little is known about the behavioral phenotype of these mice. Here we report the novel finding that hTDP-43 mice develop deficits in cognition, motor performance, and coordination. We show that these behavioral deficits are associated with the accumulation of nuclear and cytosolic TDP-43 C-terminal fragments, a decrease in endogenous TDP-43 levels, and synaptic loss. Our findings provide critical insights into disease pathology, and will help guide future preclinical studies aimed at testing the effects of potential therapeutic agents on the onset and progression of TDP-43 proteinopathies. (C) 2014 Elsevier Inc. All rights reserved.