Transgenic rat model of neurodegeneration caused by mutation in the TDP gene.
Transgenic rat model of neurodegeneration caused by mutation in the TDP gene.
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DOI：
10.1371/journal.pgen.1000887
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发表时间：
2010-03-26
期刊：
影响因子：
4.5
通讯作者：
Xia XG
中科院分区：
文献类型：
--
作者：
Zhou H;Huang C;Chen H;Wang D;Landel CP;Xia PY;Bowser R;Liu YJ;Xia XG
TDP-43蛋白病变已在广泛的神经退行性疾病中观察到。编码TDP-43的基因突变（即TDP）已在肌萎缩性侧索硬化症（ALS）和与运动神经元疾病相关的额颞叶变性中被发现。为了研究完整系统中TDP突变的后果，我们创建了表达正常人类TDP或M337V替代的人类TDP突变形式的转基因大鼠。过度表达突变而非正常的TDP可引起广泛的神经变性，主要影响运动系统。TDP突变在转基因大鼠中再现ALS表型，表现为运动神经元进行性变性和骨骼肌去神经萎缩。这个健壮的大鼠模型也重现了TDP-43蛋白病变的特征，包括TDP-43包涵体的形成、磷酸化的TDP-43的细胞质定位和TDP-43蛋白的断裂。TDP转基因大鼠将有助于破译TDP-43相关神经退行性疾病的机制。肌萎缩性侧索硬化症，也被称为Lou Gehrig's病，其特征是运动神经元进行性变性，骨骼肌去神经萎缩，最终导致受影响肢体瘫痪。Lou Gehrig病的标志性病理是细胞内包含磷酸化TDP-43蛋白的包涵体的形成。大多数Lou Gehrig病的病例没有明确的病因，而只有大约10%的病例是由个体基因突变引起的。在这里，我们描述了一种新的大鼠模型，该模型表达了编码TDP-43的人类基因的突变形式，并表现出在卢伽雷氏病患者中观察到的表型和病理特征。实验大鼠是药理学研究的首选动物。因此，这种新的大鼠模型不仅对Lou Gehrig病的机制研究有用，而且对这种毁灭性疾病的治疗方法的开发也有用。
TDP-43 proteinopathies have been observed in a wide range of neurodegenerative diseases. Mutations in the gene encoding TDP-43 (i.e., TDP) have been identified in amyotrophic lateral sclerosis (ALS) and in frontotemporal lobe degeneration associated with motor neuron disease. To study the consequences of TDP mutation in an intact system, we created transgenic rats expressing normal human TDP or a mutant form of human TDP with a M337V substitution. Overexpression of mutant, but not normal, TDP caused widespread neurodegeneration that predominantly affected the motor system. TDP mutation reproduced ALS phenotypes in transgenic rats, as seen by progressive degeneration of motor neurons and denervation atrophy of skeletal muscles. This robust rat model also recapitulated features of TDP-43 proteinopathies including the formation of TDP-43 inclusions, cytoplasmic localization of phosphorylated TDP-43, and fragmentation of TDP-43 protein. TDP transgenic rats will be useful for deciphering the mechanisms underlying TDP-43–related neurodegenerative diseases. Amyotrophic lateral sclerosis, a condition also known as Lou Gehrig's disease, is characterized by progressive degeneration of motor neurons, denervation atrophy of skeletal muscles, and eventual paralysis of affected limbs. The signature pathology of Lou Gehrig's disease is the formation of intracellular inclusions containing phosphorylated TDP-43 protein. Most cases of Lou Gehrig's disease do not have a clear cause, while only about 10% of the cases are caused by mutation of individual genes. Here, we describe a novel rat model that expresses a mutated form of the human gene encoding TDP-43 and manifests the phenotypes and pathological features observed in patients with Lou Gehrig's disease. Laboratory rats are the preferred animals for pharmacological studies. Therefore, this new rat model will be useful not only for mechanistic study of Lou Gehrig's disease, but also for the development of therapies for this devastating disease.
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影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
Brown, R. H., Jr.
影响因子：
12.7
作者：
Brandmeir, Nicholas J.;Geser, Felix;Trojanowski, John Q.
通讯作者：
Trojanowski, John Q.
影响因子：
6
作者：
Cairns, Nigel J.;Neumann, Manuela;Mackenzie, Ian R. A.
通讯作者：
Mackenzie, Ian R. A.
影响因子：
4.8
作者：
Buratti, E;Brindisi, A;Baralle, FE
通讯作者：
Baralle, FE
影响因子：
12.7
作者：
Arai, Tetsuaki;Mackenzie, Ian R. A.;Akiyama, Haruhiko
通讯作者：
Akiyama, Haruhiko