Mutant copper-zinc superoxide dismutase binds to and destabilizes human low molecular weight neurofilament mRNA
Mutant copper-zinc superoxide dismutase binds to and destabilizes human low molecular weight neurofilament mRNA
复制标题
DOI：
10.1074/jbc.m405065200
复制
发表时间：
2005-01-07
影响因子：
4.8
通讯作者：
Strong, MJ
中科院分区：
文献类型：
--
作者：
Ge, WW;Wen, WY;Strong, MJ
突变的铜锌超氧化物歧化酶 (SOD1) 导致家族性肌萎缩侧索硬化症的机制被认为涉及功能的不利获得，与 SOD1 的生理抗氧化酶性质无关。在这项研究中，我们观察到突变型 SOD1（G41S、G85A 和 G93A）而非野生型以剂量依赖性方式显着降低了低分子量神经丝 mRNA 的稳定性。我们还证明突变型 SOD1（而非野生型）直接与神经丝 mRNA 3'-非翻译区结合，并且这种结合对于诱导 mRNA 不稳定是必要的。这些观察结果为一种新的功能获得提供了解释，即运动神经元中突变的 SOD1 表达改变了中间丝蛋白的表达。
The mechanism by which mutated copper-zinc superoxide dismutase (SOD1) causes familial amyotrophic lateral sclerosis is believed to involve an adverse gain of function, independent of the physiological antioxidant enzymatic properties of SOD1. In this study, we have observed that mutant SOD1 (G41S, G85A, and G93A) but not the wild type significantly reduced the stability of the low molecular weight neurofilament mRNA in a dosage-dependent manner. We have also demonstrated that mutant SOD1 but not the wild type bound directly to the neurofilament mRNA 3'-untranslated region and that the binding was necessary to induce mRNA destabilization. These observations provide an explanation for a novel gain of function in which mutant SOD1 expression in motor neurons alters an intermediate filament protein expression.