Substantially elevating the levels of αB-crystallin in spinal motor neurons of mutant SOD1 mice does not significantly delay paralysis or attenuate mutant protein aggregation.
Substantially elevating the levels of αB-crystallin in spinal motor neurons of mutant SOD1 mice does not significantly delay paralysis or attenuate mutant protein aggregation.
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显着提高突变型 SOD1 小鼠脊髓运动神经元中 αB-晶状体蛋白的水平不会显着延迟麻痹或减弱突变蛋白聚集。
DOI：
10.1111/jnc.13022
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发表时间：
2015
影响因子：
4.7
通讯作者：
Borchelt,DavidR
中科院分区：
文献类型：
--
作者：
Xu,Guilian;Fromholt,Susan;Ayers,JacobI;Brown,Hilda;Siemienski,Zoe;Crosby,KeithW;Mayer,ChristopherA;Janus,Christopher;Borchelt,DavidR
人们对增强内源性蛋白质维持途径（如热休克分子伴侣反应）产生了极大的兴趣，因为据推测，增强错误折叠蛋白质的清除可能对肌萎缩侧索硬化和其他神经退行性疾病具有有益的疾病改善作用。在突变SOD 1聚集的培养细胞模型中，αB-晶状体蛋白（αB-crys）的共表达已显示可抑制洗涤剂不溶性形式的突变蛋白的形成。在这里，我们描述了一种新的转基因小鼠品系的产生，其在脊髓中表达的αB-crys是正常水平的6倍以上，整个脊髓灰质，特别是脊髓运动神经元中的免疫反应性显著增加。令人惊讶的是，单独表达αB-crys的小鼠的脊髓每个切片中含有的运动神经元比同窝对照多20%。在转基因G93 A或L126 Z突变SOD 1的小鼠中，将αB-crys提高这些水平对瘫痪发生的年龄没有影响。在G93 A小鼠中，运动神经元损失程度最严重，这些细胞的数量下降的比例与单独表达突变体SOD 1的小鼠相同。在瘫痪的双基因小鼠中，不溶于洗涤剂的、错误折叠的突变型SOD 1的水平与仅表达突变型SOD 1的小鼠相似。这些发现表明，将脊髓运动神经元中αB-crys水平提高6倍并不能产生突变SOD 1聚集的细胞培养模型所预测的治疗效果。增强蛋白伴侣功能可能为治疗由SOD 1突变引起的肌萎缩侧索硬化症和其他以胞质蛋白聚集为特征的神经退行性疾病提供了一种方法。先前在细胞模型中的研究表明，被称为αB-晶体蛋白（αB-crys）的分子伴侣可以防止突变SOD 1聚集。我们报道，在表达突变SOD 1的小鼠脊髓中，αB-crys的转基因表达水平是正常水平的6倍以上，但不产生治疗益处。
There has been great interest in enhancing endogenous protein maintenance pathways such as the heat‐shock chaperone response, as it is postulated that enhancing clearance of misfolded proteins could have beneficial disease modifying effects in amyotrophic lateral sclerosis and other neurodegenerative disorders. In cultured cell models of mutant SOD1 aggregation, co‐expression of αB‐crystallin (αB‐crys) has been shown to inhibit the formation of detergent‐insoluble forms of mutant protein. Here, we describe the generation of a new line of transgenic mice that express αB‐crys at > 6‐fold the normal level in spinal cord, with robust increases in immunoreactivity throughout the spinal cord grey matter and, specifically, in spinal motor neurons. Surprisingly, spinal cords of mice expressing αB‐crys alone contained 20% more motor neurons per section than littermate controls. Raising αB‐crys by these levels in mice transgenic for either G93A or L126Z mutant SOD1 had no effect on the age at which paralysis developed. In the G93A mice, which showed the most robust degree of motor neuron loss, the number of these cells declined by the same proportion as in mice expressing the mutant SOD1 alone. In paralyzed bigenic mice, the levels of detergent‐insoluble, misfolded, mutant SOD1 were similar to those of mice expressing mutant SOD1 alone. These findings indicate that raising the levels of αB‐crys in spinal motor neurons by 6‐fold does not produce the therapeutic effects predicted by cell culture models of mutant SOD1 aggregation.Enhancing the protein chaperone function may present a therapeutic approach to amyotrophic lateral sclerosis caused by mutations in SOD1, and other neurodegenerative disorders characterized by cytosolic protein aggregation. Previous studies in cell models suggested that the chaperone known as αB‐crystallin (αB‐crys) can prevent mutant SOD1 aggregation. We report that transgenic expression of αB‐crys at > 6‐fold the normal level in spinal cords of mice expressing mutant SOD1 produces no therapeutic benefit.