Increased Ubqln2 expression causes neuron death in transgenic rats.
Increased Ubqln2 expression causes neuron death in transgenic rats.
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DOI：
10.1111/jnc.13748
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发表时间：
2016-10
影响因子：
4.7
通讯作者：
Xia XG
中科院分区：
文献类型：
--
作者：
Huang B;Wu Q;Zhou H;Huang C;Xia XG
泛素连接酶2（UBQLN2）的致病性突变会导致肌萎缩侧索硬化症和额颞叶痴呆中的神经退行性变。UBQLN2突变如何导致这些疾病尚不清楚。虽然在啮齿动物模型中，带有致病性突变的UBQLN2过表达会导致神经元死亡，但大鼠中Ubqln2的缺失对神经元功能没有影响。先前在动物模型中的研究结果表明，UBQLN2突变主要是通过功能获得而非功能丧失导致疾病。为了检验UBQLN2突变中的毒性功能获得是否与UBQLN2功能增强有关，我们构建了过表达野生型人UBQLN2的新型转基因大鼠。考虑到人UBQLN2在大鼠基因组中可能无法正常发挥功能，我们还构建了过表达大鼠自身Ubqln2的转基因大鼠。当在大鼠中过表达时，人和大鼠的野生型Ubqln2都会导致神经元死亡和空间学习缺陷，这些病理变化与在突变型UBQLN2转基因大鼠中观察到的无法区分。过表达的野生型UBQLN2形成蛋白质聚集体，吸引自噬底物p62和蛋白酶体成分Rpt1。这些发现表明，过量的UBQLN2对神经元是有毒性的而非保护性的，并且UBQLN2功能的增强与UBQLN2的发病机制有关。
泛素连接酶2（UBQLN2）的致病性突变会导致肌萎缩侧索硬化症和额颞叶痴呆中的神经退行性变。在啮齿动物模型中的研究表明突变型UBQLN2具有毒性功能获得。我们构建了新的转基因大鼠作为相关模型，并检验了增强野生型UBQLN2的表达是否与突变型UBQLN2的发病机制有关。我们观察到在转基因大鼠中，人或大鼠野生型Ubqln2的过表达会导致蛋白质聚集和神经元死亡。我们的研究结果表明，过量的UBQLN2对神经元是有毒性的而非保护性的，并且UBQLN2功能的不受控制的增强与UBQLN2的发病机制有关。
Pathogenic mutation of ubiquilin 2 (UBQLN2) causes neurodegeneration in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. How UBQLN2 mutations cause the diseases is not clear. While overexpression of UBQLN2 with pathogenic mutation causes neuron death in rodent models, deletion of the Ubqln2 in rats has no effect on neuronal function. Previous findings in animal models suggest that UBQLN2 mutations cause the diseases mainly through a gain rather than a loss of functions. To examine whether the toxic gain in UBQLN2 mutation is related to the enhancement of UBQLN2 functions, we created new transgenic rats overexpressing wildtype human UBQLN2. Considering that human UBQLN2 may not function properly in the rat genome, we also created transgenic rats overexpressing rat own Ubqln2. When overexpressed in rats, both human and rat wildtype Ubqln2 caused neuronal death and spatial learning deficits, the pathologies that were indistinguishable from those observed in mutant UBQLN2 transgenic rats. Overexpressed wildtype UBQLN2 formed protein inclusions attracting the autophagy substrate p62 and the proteasome component Rpt1. These findings suggest that excess UBQLN2 is toxic rather than protective to neurons and that the enhancement of UBQLN2 functions is involved in UBQLN2 pathogenesis. Pathogenic mutation in Ubiquilin 2 (UBQLN2) causes neurodegeneration in ALS and FTLD. Studies in rodent models suggest a gain of toxic function in mutant UBQLN2. We created new transgenic rats as a relevant model and examined whether enhancing wildtype UBQLN2 expression is implicated in the pathogenesis of mutant UBQLN2. We observed that overexpression of human or rat wildtype Ubqln2 caused protein aggregation and neuronal death in transgenic rats. Our findings suggest that excess UBQLN2 is toxic rather than protective to neurons and that uncontrolled enhancement of UBQLN2 function is involved in UBQLN2 pathogenesis.
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影响因子：
12.7
作者：
Wu Q;Liu M;Huang C;Liu X;Huang B;Li N;Zhou H;Xia XG
通讯作者：
Xia XG
影响因子：
12.7
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
通讯作者：
Shaw CE
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/s0167-4889(01)00164-1
发表时间：
2002-01-30
影响因子：
5.1
作者：
Wu, SL;Mikhailov, A;Avruch, J
通讯作者：
Avruch, J
影响因子：
16
作者：
Kleijnen, MF;Shih, AH;Howley, PM
通讯作者：
Howley, PM