Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion.
Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion.
复制标题
DOI：
10.1007/s00401-012-1043-z
复制
发表时间：
2013-02
影响因子：
12.7
通讯作者：
Shaw CE
中科院分区：
文献类型：
--
作者：
Mitchell JC;McGoldrick P;Vance C;Hortobagyi T;Sreedharan J;Rogelj B;Tudor EL;Smith BN;Klasen C;Miller CC;Cooper JD;Greensmith L;Shaw CE
肌萎缩侧索硬化症（ALS）和额颞叶变性（FTLD）是一种持续进行的神经退行性疾病，具有重叠的临床，遗传和病理特征。融合肉瘤（FUS）的细胞质内含物是FUS基因突变的几种形式的FTLD和ALS患者的标志。FUS是一种多功能的，主要是核，DNA和RNA结合蛋白。在这里，我们报告说，转基因小鼠过度表达野生型人类FUS开发一个积极的表型与早发性震颤，随后进行性后肢瘫痪和纯合子动物死亡12周。大的运动神经元从脊髓中丢失，伴随着去神经支配和局灶性肌肉萎缩的神经生理学证据。脊髓中存活的运动神经元细胞质中FUS的表达大大增加，球状和绞样FUS阳性和泛素阴性包涵体与星形胶质细胞和小胶质细胞反应性相关。在转基因小鼠的脑中也检测到细胞质FUS包涵体，而没有明显的神经元损失和很少的星形胶质细胞或小胶质细胞活化。半合子FUS过表达小鼠没有表现出运动表型或病理学的证据。这些发现概括了在人类ALS和FTLD患者中观察到的几种病理特征，并表明脆弱神经元中野生型FUS的过度表达可能是疾病的根本原因之一。此外，这些小鼠将为研究疾病机制和测试治疗提供新的模型。本文的在线版本（doi：10.1007/s 00401 -012-1043-z）包含补充材料，可供授权用户使用。
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are relentlessly progressive neurodegenerative disorders with overlapping clinical, genetic and pathological features. Cytoplasmic inclusions of fused in sarcoma (FUS) are the hallmark of several forms of FTLD and ALS patients with mutations in the FUS gene. FUS is a multifunctional, predominantly nuclear, DNA and RNA binding protein. Here, we report that transgenic mice overexpressing wild-type human FUS develop an aggressive phenotype with an early onset tremor followed by progressive hind limb paralysis and death by 12 weeks in homozygous animals. Large motor neurons were lost from the spinal cord accompanied by neurophysiological evidence of denervation and focal muscle atrophy. Surviving motor neurons in the spinal cord had greatly increased cytoplasmic expression of FUS, with globular and skein-like FUS-positive and ubiquitin-negative inclusions associated with astroglial and microglial reactivity. Cytoplasmic FUS inclusions were also detected in the brain of transgenic mice without apparent neuronal loss and little astroglial or microglial activation. Hemizygous FUS overexpressing mice showed no evidence of a motor phenotype or pathology. These findings recapitulate several pathological features seen in human ALS and FTLD patients, and suggest that overexpression of wild-type FUS in vulnerable neurons may be one of the root causes of disease. Furthermore, these mice will provide a new model to study disease mechanism, and test therapies. The online version of this article (doi:10.1007/s00401-012-1043-z) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
4.2
作者：
Gal J;Zhang J;Kwinter DM;Zhai J;Jia H;Jia J;Zhu H
通讯作者：
Zhu H
影响因子：
3.4
作者：
Guillemin, I;Becker, M;Nothwang, HG
通讯作者：
Nothwang, HG
影响因子：
9.8
作者：
Ju S;Tardiff DF;Han H;Divya K;Zhong Q;Maquat LE;Bosco DA;Hayward LJ;Brown RH Jr;Lindquist S;Ringe D;Petsko GA
通讯作者：
Petsko GA
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.
DOI：
10.1016/s1050-3862(96)00167-2
发表时间：
1996-12-01
期刊：
GENETIC ANALYSIS-BIOMOLECULAR ENGINEERING
影响因子：
--
作者：
Borchelt, DR;Davis, J;Price, DL
通讯作者：
Price, DL