Frontiers | Copper Toxicity and Deficiency: The Vicious Cycle at the Core of Protein Aggregation in ALS

IF 3.5 3区 医学 Q2 NEUROSCIENCES
Jin-Hong Min, Robert A. Harris, Heela Sarlus
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引用次数: 0

Abstract

The pathophysiology of ALS involves many signs of a disruption in copper homeostasis, with both excess free levels and functional deficiency likely occurring simultaneously. This is crucial, as many important physiological functions are performed by cuproenzymes. While it is unsurprising that many ALS symptoms are related to signs of copper deficiency, resulting in vascular, antioxidant system and mitochondrial oxidative respiration deficiencies, there are also signs of copper toxicity such as ROS generation and enhanced protein aggregation. We discuss how copper also plays a key role in proteostasis and interacts either directly or indirectly with many of the key aggregate-prone proteins implicated in ALS, such as TDP-43, C9ORF72, SOD1 and FUS as well as the effect of their aggregation on copper homeostasis. We suggest that loss of cuproprotein function is at the core of ALS pathology, a condition that is driven by a combination of unbound copper and ROS that can either initiate and/or accelerate protein aggregation. This could trigger a positive feedback cycle whereby protein aggregates trigger the aggregation of other proteins in a chain reaction that eventually captures elements of the proteostatic mechanisms in place to counteract them. The end result is an abundance of aggregated non-functional cuproproteins and chaperones alongside depleted intracellular copper stores, resulting in a general lack of cuproenzyme function. We then discuss the possible aetiology of ALS and illustrate how strong risk factors including environmental toxins such as BMAA and heavy metals can functionally behave to promote protein aggregation and disturb copper metabolism that likely drives this vicious cycle in sporadic ALS. From this synthesis, we propose restoration of copper balance using copper delivery agents in combination with chaperones/chaperone mimetics, perhaps in conjunction with the neuroprotective amino acid serine, as a promising strategy in the treatment of this incurable disease.
铜的毒性和缺乏:ALS蛋白聚集核心的恶性循环
渐冻人症的病理生理学涉及铜平衡紊乱的许多迹象,游离水平过高和功能性缺乏可能同时发生。这一点至关重要,因为许多重要的生理功能都是由铜酵素实现的。许多渐冻人症的症状与铜缺乏有关,导致血管、抗氧化系统和线粒体氧化呼吸不足,这一点不足为奇,但同时也存在铜中毒的迹象,如 ROS 生成和蛋白质聚集增强。我们讨论了铜如何在蛋白稳态中发挥关键作用,如何直接或间接与许多与 ALS 有关的易聚集的关键蛋白(如 TDP-43、C9ORF72、SOD1 和 FUS)相互作用,以及它们的聚集对铜稳态的影响。我们认为,铜蛋白功能的丧失是渐冻症病理学的核心,这种病症是由未结合的铜和 ROS 共同驱动的,而 ROS 可以启动和/或加速蛋白质的聚集。这可能会引发一种正反馈循环,即蛋白质聚集引发其他蛋白质的聚集,这种连锁反应最终会捕捉到蛋白质静态机制中的元素来抵消它们。最终的结果是,大量聚集的无功能铜蛋白和伴侣蛋白以及细胞内铜储存耗尽,导致铜酵素功能普遍缺乏。然后,我们讨论了渐冻症的可能病因,并说明了包括环境毒素(如 BMAA 和重金属)在内的强风险因素如何在功能上促进蛋白质聚集和扰乱铜代谢,从而可能在散发性渐冻症中推动这一恶性循环。综上所述,我们建议将铜输送剂与伴侣蛋白/伴侣蛋白仿制药结合使用,或许与神经保护性氨基酸丝氨酸结合使用,以恢复铜平衡,作为治疗这种不治之症的一种有前途的策略。
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来源期刊
CiteScore
5.70
自引率
2.10%
发文量
669
审稿时长
14 weeks
期刊介绍: Frontiers in Molecular Neuroscience is a first-tier electronic journal devoted to identifying key molecules, as well as their functions and interactions, that underlie the structure, design and function of the brain across all levels. The scope of our journal encompasses synaptic and cellular proteins, coding and non-coding RNA, and molecular mechanisms regulating cellular and dendritic RNA translation. In recent years, a plethora of new cellular and synaptic players have been identified from reduced systems, such as neuronal cultures, but the relevance of these molecules in terms of cellular and synaptic function and plasticity in the living brain and its circuits has not been validated. The effects of spine growth and density observed using gene products identified from in vitro work are frequently not reproduced in vivo. Our journal is particularly interested in studies on genetically engineered model organisms (C. elegans, Drosophila, mouse), in which alterations in key molecules underlying cellular and synaptic function and plasticity produce defined anatomical, physiological and behavioral changes. In the mouse, genetic alterations limited to particular neural circuits (olfactory bulb, motor cortex, cortical layers, hippocampal subfields, cerebellum), preferably regulated in time and on demand, are of special interest, as they sidestep potential compensatory developmental effects.
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