Few proteins have come under such intense scrutiny as superoxide dismutase-1 (SOD1). For almost a century, scientists have dissected its form, function and then later its malfunction in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We now know SOD1 is a zinc and copper metalloenzyme that clears superoxide as part of our antioxidant defence and respiratory regulation systems. The possibility of reduced structural integrity was suggested by the first crystal structures of human SOD1 even before deleterious mutations in thesod1gene were linked to the ALS. This concept evolved in the intervening years as an impressive array of biophysical studies examined the characteristics of mutant SOD1 in great detail. We now recognise how ALS-related mutations perturb the SOD1 maturation processes, reduce its ability to fold and reduce its thermal stability and half-life. Mutant SOD1 is therefore predisposed to monomerisation, non-canonical self-interactions, the formation of small misfolded oligomers and ultimately accumulation in the tell-tale insoluble inclusions found within the neurons of ALS patients. We have also seen that several post-translational modifications could push wild-type SOD1 down this toxic pathway. Recently we have come to view ALS as a prion-like disease where both the symptoms, and indeed SOD1 misfolding itself, are transmitted to neighbouring cells. This raises the possibility of intervention after the initial disease presentation. Several small-molecule and biologic-based strategies have been devised which directly target the SOD1 molecule to change the behaviour thought to be responsible for ALS. Here we provide a comprehensive review of the many biophysical advances that sculpted our view of SOD1 biology and the recent work that aims to apply this knowledge for therapeutic outcomes in ALS.

中文翻译：

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超氧化物歧化酶-1与肌萎缩侧索硬化的生物物理学

很少有蛋白质像超氧​​化物歧化酶-1 (SOD1) 那样受到如此严格的审查。近一个世纪以来，科学家们已经剖析了它的形式、功能以及后来它在神经退行性疾病肌萎缩侧索硬化症 (ALS) 中的功能障碍。我们现在知道 SOD1 是一种锌和铜金属酶，它可以清除超氧化物，作为我们抗氧化防御和呼吸调节系统的一部分。人类 SOD1 的第一个晶体结构甚至在 SOD1 的有害突变之前就表明了结构完整性降低的可能性。草皮1基因与ALS有关。随着一系列令人印象深刻的生物物理学研究对突变 SOD1 的特征进行了非常详细的研究，这一概念在随后的几年中得到了发展。我们现在认识到 ALS 相关突变如何扰乱 SOD1 成熟过程，降低其折叠能力并降低其热稳定性和半衰期。因此，突变体 SOD1 倾向于单体化、非规范的自我相互作用、小的错误折叠寡聚体的形成，并最终在 ALS 患者神经元内发现的不溶性包涵体中积累。我们还看到，一些翻译后修饰可以将野生型 SOD1 推下这条有毒途径。最近，我们开始将 ALS 视为一种类似朊病毒的疾病，其症状，实际上是 SOD1 错误折叠本身，都会传播到邻近的细胞。这增加了在最初疾病出现后进行干预的可能性。已经设计了几种小分子和基于生物的策略，直接针对 SOD1 分子以改变被认为是导致 ALS 的行为。在这里，我们全面回顾了塑造我们对 SOD1 生物学观点的许多生物物理学进展，以及最近旨在将这些知识应用于 ALS 治疗结果的工作。