A misfolded dimer of Cu/Zn-superoxide dismutase leading to pathological oligomerization in amyotrophic lateral sclerosis
A misfolded dimer of Cu/Zn-superoxide dismutase leading to pathological oligomerization in amyotrophic lateral sclerosis
复制标题
DOI：
10.1002/pro.3094
复制
发表时间：
2017-03-01
期刊：
影响因子：
8
通讯作者：
Furukawa, Yoshiaki
中科院分区：
文献类型：
--
作者：
Anzai, Itsuki;Tokuda, Eiichi;Furukawa, Yoshiaki
突变的铜/锌超氧化物歧化酶(SOD1)的错误折叠是肌萎缩侧索硬化症家族性形式的病理标志。致病突变被认为是在正常情况下采用同源二聚体构型使SOD1单体，然后触发SOD1蛋白的异常寡聚。尽管如此，在生理条件下导致齐聚的SOD1的错误折叠构象仍然是模糊的。在这里，我们表明，在体温(类似于37摄氏度)附近，突变体SOD1保持二聚体构型，但缺乏大部分二级结构。此外，这种异常的SOD1二聚体具有明显的结构无序，容易形成通过二硫键交联的不可逆低聚物。在表达突变SOD1的患病小鼠的脊髓中检测到SOD1的二硫键交联的寡聚体。因此，我们提出了突变的SOD1错误折叠的另一种途径，这是导致该病病理中寡聚化的原因。
Misfolding of mutant Cu/Zn-superoxide dismutase (SOD1) is a pathological hallmark in a familial form of amyotrophic lateral sclerosis. Pathogenic mutations have been proposed to monomerize SOD1 normally adopting a homodimeric configuration and then trigger abnormal oligomerization of SOD1 proteins. Despite this, a misfolded conformation of SOD1 leading to the oligomerization at physiological conditions still remains ambiguous. Here, we show that, around the body temperature (similar to 37 degrees C), mutant SOD1 maintains a dimeric configuration but lacks most of its secondary structures. Also, such an abnormal SOD1 dimer with significant structural disorder was prone to irreversibly forming the oligomers crosslinked via disulfide bonds. The disulfide-crosslinked oligomers of SOD1 were detected in the spinal cords of the diseased mice expressing mutant SOD1. We hence propose an alternative pathway of mutant SOD1 misfolding that is responsible for oligomerization in the pathologies of the disease.