Hilton James B W, Kysenius Kai, Liddell Jeffrey R, Mercer Stephen W, Paul Bence, Beckman Joseph S, McLean Catriona A, White Anthony R, Donnelly Paul S, Bush Ashley I, Hare Dominic J, Roberts Blaine R, Crouch Peter J
Department of Anatomy and Physiology, The University of Melbourne, Victoria, 3010, Australia.
School of Geography, Earth and Atmospheric Sciences, The University of Melbourne, Victoria, 3010, Australia.
Sci Rep. 2024 Mar 11;14(1):5929. doi: 10.1038/s41598-024-55832-w.
The copper compound Cu(atsm) has progressed to phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Cu(atsm) is neuroprotective in mutant SOD1 mouse models of ALS where its activity is ascribed in part to improving availability of essential copper. However, SOD1 mutations cause only ~ 2% of ALS cases and therapeutic relevance of copper availability in sporadic ALS is unresolved. Herein we assessed spinal cord tissue from human cases of sporadic ALS for copper-related changes. We found that when compared to control cases the natural distribution of spinal cord copper was disrupted in sporadic ALS. A standout feature was decreased copper levels in the ventral grey matter, the primary anatomical site of neuronal loss in ALS. Altered expression of genes involved in copper handling indicated disrupted copper availability, and this was evident in decreased copper-dependent ferroxidase activity despite increased abundance of the ferroxidases ceruloplasmin and hephaestin. Mice expressing mutant SOD1 recapitulate salient features of ALS and the unsatiated requirement for copper in these mice is a biochemical target for Cu(atsm). Our results from human spinal cord indicate a therapeutic mechanism of action for Cu(atsm) involving copper availability may also be pertinent to sporadic cases of ALS.
铜化合物Cu(atsm)已进入治疗神经退行性疾病肌萎缩侧索硬化症（ALS）的2/3期试验。在ALS的突变SOD1小鼠模型中，Cu(atsm)具有神经保护作用，其活性部分归因于提高必需铜的利用率。然而，SOD1突变仅导致约2%的ALS病例，散发性ALS中铜利用率的治疗相关性尚未明确。在此，我们评估了散发性ALS患者脊髓组织中与铜相关的变化。我们发现，与对照病例相比，散发性ALS患者脊髓铜的自然分布受到破坏。一个突出的特征是腹侧灰质中的铜水平降低，腹侧灰质是ALS中神经元丧失的主要解剖部位。参与铜处理的基因表达改变表明铜利用率受到破坏，这在铜依赖性铁氧化酶活性降低中很明显，尽管铁氧化酶铜蓝蛋白和铁转运蛋白的丰度增加。表达突变SOD1的小鼠重现了ALS的显著特征，这些小鼠对铜的未满足需求是Cu(atsm)的生化靶点。我们从人类脊髓获得的结果表明，Cu(atsm)涉及铜利用率的治疗作用机制可能也适用于散发性ALS病例。
