Misfolded SOD1 forms high-density molecular complexes with synaptic molecules in mutant SOD1-linked familial amyotrophic lateral sclerosis cases
Misfolded SOD1 forms high-density molecular complexes with synaptic molecules in mutant SOD1-linked familial amyotrophic lateral sclerosis cases
复制标题
DOI：
10.1016/j.jns.2011.10.017
复制
发表时间：
2012-03-15
影响因子：
4.4
通讯作者：
Arima, Kunimasa
中科院分区：
文献类型：
--
作者：
Araki, Toshiyuki;Nagano, Seiichi;Arima, Kunimasa
超氧化物歧化酶1（sod 1）基因突变导致家族性肌萎缩侧索硬化症（familial amyotrophic lateral sclerosis，FALS），可能是由于错误折叠的突变SOD 1蛋白的毒性。在这里，我们报告识别的各种突触分子形成分子复合物与错误折叠的SOD 1突变体SOD 1相关的患者组织，以及在细胞的FALS模型。在FALS细胞模型系统中，我们发现模仿突触超活化/兴奋性毒性的膜去极化可导致突变SOD的错误折叠，以及错误折叠的SOD 1-突触蛋白复合物形成的加速。这些结果表明，通过错误折叠的SOD 1与突触分子的关联抑制突触释放机制在FALS功能障碍中起作用。(C)2011 Elsevier B. V.保留所有权利。
Mutations in the superoxide dismutase 1 (sod1) gene cause familial amyotrophic lateral sclerosis (FALS), likely due to the toxic properties of misfolded mutant SOD1 protein. Here we report identification of various synaptic molecules forming molecular complexes with misfolded SOD1 in mutant SOD1-associated FALS patient tissues as well as in cellular FALS models. In the FALS cellular model system, we found that membrane depolarization that mimics synaptic hyperactivation/excitotoxicity could cause misfolding of mutant SOD, as well as acceleration of misfolded SOD1-synaptic protein complex formation. These results suggest that inhibition of synaptic release mechanism by association of misfolded SOD1 with synaptic molecules plays a role in the dysfunction of FALS. (C) 2011 Elsevier B.V. All rights reserved.