Pathogenic Ubqln2 gains toxic properties to induce neuron death.
Pathogenic Ubqln2 gains toxic properties to induce neuron death.
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DOI：
10.1007/s00401-014-1367-y
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发表时间：
2015-03
影响因子：
12.7
通讯作者：
Xia XG
中科院分区：
文献类型：
--
作者：
Wu Q;Liu M;Huang C;Liu X;Huang B;Li N;Zhou H;Xia XG
泛素 2 (Ubqln2) 突变与肌萎缩侧索硬化症和额颞叶变性有关。关于 Ubqln2 发病机制的一个首要问题是 Ubqln2 致病性突变是否会通过功能的获得或丧失导致神经元死亡。为了更好地了解 Ubqln2 病理学，我们创建了 Ubqln2 转基因和敲除大鼠，并比较了这些新型大鼠模型中的表型表达。具有致病性突变（P497H 取代）的 Ubqln2 过度表达导致 130 天龄转基因大鼠认知缺陷和神经元损失。在转基因大鼠中，神经元损失先于 Ubqln2 聚集体的逐渐形成，并伴随着自噬底物 p62 和 LC3-II 的逐渐积累以及内体途径的损伤。相比之下，在 300 天龄的 Ubqln2 敲除大鼠中未检测到在突变型 Ubqln2 转基因大鼠中观察到的这些病理。总之，我们在 Ubqln2 转基因和敲除大鼠中的研究结果共同表明，致病性 Ubqln2 主要通过获得未揭示的功能而不是丧失生理功能来导致神经元死亡。
Mutations in ubiquilin 2 (Ubqln2) is linked to amyotrophic lateral sclerosis and frontotemporal lobar degeneration. A foremost question regarding Ubqln2 pathogenesis is whether pathogenically mutated Ubqln2 causes neuron death via a gain or loss of functions. To better understand Ubqln2 pathobiology, we created Ubqln2 transgenic and knockout rats and compared phenotypic expression in these novel rat models. Overexpression of Ubqln2 with a pathogenic mutation (P497H substitution) caused cognitive deficits and neuronal loss in transgenic rats at the age of 130 days. In the transgenic rats, neuronal loss was preceded by the progressive formation of Ubqln2 aggregates and was accompanied by the progressive accumulation of the autophagy substrates p62 and LC3-II and the impairment of endosome pathways. In contrast, none of these pathologies observed in mutant Ubqln2 transgenic rats was detected in Ubqln2 knockout rats at the age of 300 days. Together, our findings in Ubqln2 transgenic and knockout rats collectively suggest that pathogenic Ubqln2 causes neuron death mainly through a gain of unrevealed functions rather than a loss of physiological functions.