An examination of αB-crystallin as a modifier of SOD1 aggregate pathology and toxicity in models of familial amyotrophic lateral sclerosis
An examination of αB-crystallin as a modifier of SOD1 aggregate pathology and toxicity in models of familial amyotrophic lateral sclerosis
复制标题
DOI：
10.1111/j.1471-4159.2010.06572.x
复制
发表时间：
2010-06-01
影响因子：
4.7
通讯作者：
Borchelt, David R.
中科院分区：
文献类型：
--
作者：
Karch, Celeste M.;Borchelt, David R.
P>肌萎缩侧索硬化症是一种进行性麻痹性神经退行性疾病，可能由 Cu,Zn-超氧化物歧化酶 1 (SOD1) 突变引起。过度表达突变型 SOD1 的转基因小鼠会出现瘫痪，并在脑干和脊髓中积聚突变蛋白。本研究使用细胞培养模型来证明 α B-晶状体蛋白能够减少突变型 SOD1 的聚集。为了测试 α B-晶状体蛋白在体内调节 SOD1 聚集的作用，将 α B-晶状体蛋白缺陷小鼠与表达两种不同 SOD1 突变体（G37R 和 L126Z）的小鼠交配。尽管在表达任一突变体的小鼠中完全消除αB-晶状体蛋白将疾病末期的间隔缩短了20-30天，但在有症状的小鼠的脊髓中可沉积的SOD1聚集物的水平没有检测到变化。由于 α B-晶状体蛋白在肌肉中表达最丰富，因此我们预计该伴侣的丧失将使该组织容易受到突变型 SOD1 聚集的影响。然而，没有证据表明突变型 SOD1 在缺乏 α B-晶状体蛋白的小鼠肌肉中聚集。我们的研究结果表明，对肌肉蛋白质稳态网络的显着扰动不足以诱导错误折叠突变体 SOD1 的聚集。这些结果对伴侣在调节错误折叠 SOD1 的组织特异性积累中的作用具有影响。
P>Amyotrophic lateral sclerosis is a progressively paralytic neurodegenerative disease that can be caused by mutations in Cu,Zn-superoxide dismutase 1 (SOD1). Transgenic mice that over-express mutant SOD1 develop paralysis and accumulate aggregates of mutant protein in the brainstem and spinal cord. The present study uses a cell culture model to demonstrate alpha B-crystallin is capable of reducing aggregation of mutant SOD1. To test the role of alpha B-crystallin in modulating SOD1 aggregation in vivo, alpha B-crystallin deficient mice were bred to mice expressing two different SOD1 mutants (G37R and L126Z). Although completely eliminating alpha B-crystallin reduced the interval to disease endstage by 20-30 days in mice expressing either mutant, there were no detectable changes in the levels of sedimentable, SOD1 aggregates in the spinal cord of symptomatic mice. Because alpha B-crystallin is most abundantly expressed in muscle, we expected that the loss of this chaperone would leave this tissue vulnerable to mutant SOD1 aggregation. However, there was no evidence of mutant SOD1 aggregation in the muscle of mice lacking alpha B-crystallin. Our findings indicate that a significant perturbation to the protein homeostasis network of muscle is not sufficient to induce the aggregation of misfolded mutant SOD1. These outcomes have implications regarding the role of chaperones in modulating the tissue specific accumulations of misfolded SOD1.