Shared molecular pathologies between distinct neurodegenerative disorders offer unique opportunities to identify common mechanisms of neuron death, and apply lessons learned from one disease to another. Neurotoxic superoxide dismutase 1 (SOD1) proteinopathy inSOD1-associated familial amyotrophic lateral sclerosis (fALS) is recapitulated in idiopathic Parkinson disease (PD), suggesting that these two phenotypically distinct disorders share an etiological pathway, and tractable therapeutic target(s). Despite 25 years of research, the molecular determinants underlying SOD1 misfolding and toxicity in fALS remain poorly understood. The absence ofSOD1mutations in PD highlights mounting evidence thatSOD1mutations are not the sole cause of SOD1 protein misfolding occasioning oligomerization and toxicity, reinforcing the importance of non-genetic factors, including protein metallation and post-translational modification in determining SOD1 stability and function. We propose that these non-genetic factors underlie the misfolding and dysfunction of SOD1 and other proteins in both PD and fALS, constituting a shared and tractable pathway to neurodegeneration.

中文翻译：

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一种拟议的机制，以金属动态平衡和氧化应激为特征的运动障碍神经变性。

在不同的神经退行性疾病之间共享的分子病理学为识别神经元死亡的常见机制，并将从一种疾病中学到的教训应用于另一种疾病提供了独特的机会。在特发性帕金森病（PD）中概括了与SOD1相关的家族性肌萎缩性侧索硬化症（fALS）中的神经毒性超氧化物歧化酶1（SOD1）蛋白病，这表明这两种在表型上不同的疾病具有共同的病因学途径和可治疗的治疗目标。尽管进行了25年的研究，但对于fALS中SOD1错折叠和毒性的分子决定因素仍然知之甚少。PD中不存在SOD1突变，这突显出越来越多的证据表明，SOD1突变并不是导致寡聚化和毒性的SOD1蛋白错误折叠的唯一原因，从而增强了非遗传因素的重要性，包括蛋白质金属化和翻译后修饰，以确定SOD1的稳定性和功能。我们提出，这些非遗传因素是PD和fALS中SOD1和其他蛋白质的错误折叠和功能障碍的基础，构成了神经退行性疾病的共享且易处理的途径。