FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration.
FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration.
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DOI：
10.1371/journal.pgen.1002011
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发表时间：
2011-03
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：
Huang C;Zhou H;Tong J;Chen H;Liu YJ;Wang D;Wei X;Xia XG
融合性肉瘤（FUS）蛋白病是额颞叶痴呆（FTLD）的一个特征，FUS基因突变与FTLD和肌萎缩侧索硬化（ALS）分离。为了研究fus基因突变的后果，我们建立了表达有或没有突变的人fus基因的转基因大鼠。过表达突变体（R521C取代），但不正常，人FUS诱导类似ALS的进行性瘫痪。突变FUS转基因大鼠发生继发于运动轴突变性的进行性瘫痪，并显示皮质和海马神经元的大量丢失。这种神经元的损失伴随着泛素聚集和胶质反应。虽然过度表达野生型人类FUS的转基因大鼠在年轻时没有症状，但在老年时，它们表现出空间学习和记忆的缺陷以及皮质和海马神经元的显著损失。这些结果表明，突变FUS比正常FUS对神经元的毒性更大，并且正常FUS的表达增加足以诱导神经元死亡。FUS转基因大鼠复制了ALS和FTLD的某些表型，为FUS相关疾病的机制研究提供了一个有用的模型。肌萎缩侧索硬化症和额颞叶变性是两种相关的疾病，其特征在于选定的神经元细胞群的变性。这两种疾病都没有明确的病因，目前都无法治愈。fus基因的突变最近被认为与这两种疾病有关。在这里，我们描述了一种新的大鼠模型，表达突变形式的人类fus基因，并表现出肌萎缩侧索硬化症和额颞叶变性的表型和病理特征。FUS转基因大鼠模型的建立不仅为FUS相关疾病的机制研究提供了可能，而且为快速开发治疗这些毁灭性疾病的方法提供了可能。
Fused in Sarcoma (FUS) proteinopathy is a feature of frontotemporal lobar dementia (FTLD), and mutation of the fus gene segregates with FTLD and amyotrophic lateral sclerosis (ALS). To study the consequences of mutation in the fus gene, we created transgenic rats expressing the human fus gene with or without mutation. Overexpression of a mutant (R521C substitution), but not normal, human FUS induced progressive paralysis resembling ALS. Mutant FUS transgenic rats developed progressive paralysis secondary to degeneration of motor axons and displayed a substantial loss of neurons in the cortex and hippocampus. This neuronal loss was accompanied by ubiquitin aggregation and glial reaction. While transgenic rats that overexpressed the wild-type human FUS were asymptomatic at young ages, they showed a deficit in spatial learning and memory and a significant loss of cortical and hippocampal neurons at advanced ages. These results suggest that mutant FUS is more toxic to neurons than normal FUS and that increased expression of normal FUS is sufficient to induce neuron death. Our FUS transgenic rats reproduced some phenotypes of ALS and FTLD and will provide a useful model for mechanistic studies of FUS–related diseases. Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are two related diseases characterized by degeneration of selected groups of neuronal cells. Neither of these diseases has a clear cause, and both are incurable at present. Mutation of the fus gene has recently been linked to these two diseases. Here, we describe a novel rat model that expresses a mutated form of the human fus gene and manifests the phenotypes and pathological features of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Establishment of this FUS transgenic rat model will allow not only for mechanistic study of FUS–related diseases, but also for quick development of therapies for these devastating diseases.
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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：
14.5
作者：
Neumann, Manuela;Rademakers, Rosa;Mackenzie, Ian R. A.
通讯作者：
Mackenzie, Ian R. A.
影响因子：
12.7
作者：
Nishihira, Yasushi;Tan, Chun-Feng;Takahashi, Hitoshi
通讯作者：
Takahashi, Hitoshi
影响因子：
11.4
作者：
Kuroda, M;Sok, J;Ron, D
通讯作者：
Ron, D
影响因子：
4.2
作者：
Drepper, Carsten;Herrmann, Thomas;Sendtner, Michael
通讯作者：
Sendtner, Michael