Petillon Camille, Hergesheimer Rudolf, Puy Hervé, Corcia Philippe, Vourc'h Patrick, Andres Christian, Karim Zoubida, Blasco Hélène
Laboratoire de Biochimie, CHRU de Tours, Tours, France.
INSERM, U1253, Université de Tours, Tours, France.
Front Neurosci. 2019 Jan 15;12:1031. doi: 10.3389/fnins.2018.01031. eCollection 2018.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the loss of motor neurons. Its etiology remains unknown, but several pathophysiological mechanisms are beginning to explain motor neuronal death, as well as oxidative stress. Iron accumulation has been observed in both sporadic and familial forms of ALS, including mouse models. Therefore, the dysregulation of iron metabolism could play a role in the pathological oxidative stress in ALS. Several studies have been undertaken to describe iron-related metabolic markers, in most cases focusing on metabolites in the bloodstream due to few available data in the central nervous system. Reports of accumulation of iron, high serum ferritin, and low serum transferrin levels in ALS patients have encouraged researchers to consider dysregulated iron metabolism as an integral part of ALS pathophysiology. However, it appears complicated to suggest a general mechanism due to the diversity of models and iron markers studied, including the lack of consensus among all of the studies. Regarding clinical study reports, most of them do not take into account confusion biases such as inflammation, renal dysfunction, and nutritional status. Furthermore, the iron regulatory pathways, particularly involving hepcidin, have not been thoroughly explored yet within the pathogenesis of iron overload in ALS. In this sense, it is also essential to explore the relation between iron overload and other ALS-related events, such as neuro-inflammation, protein aggregation, and iron-driven cell death, termed ferroptosis. In this review, we point out limits of the designs of certain studies that may prevent the understanding of the role of iron in ALS and discuss the relevance of the published data regarding the pathogenic impact of iron metabolism deregulation in this disease and the therapeutics targeting this pathway.
肌萎缩侧索硬化症（ALS）是一种由运动神经元丧失引起的神经退行性疾病。其病因尚不清楚，但一些病理生理机制已开始解释运动神经元死亡以及氧化应激。在散发性和家族性ALS中均观察到铁蓄积，包括小鼠模型。因此，铁代谢失调可能在ALS的病理性氧化应激中起作用。已经开展了多项研究来描述与铁相关的代谢标志物，在大多数情况下，由于中枢神经系统中可用数据较少，研究重点是血液中的代谢物。关于ALS患者铁蓄积、高血清铁蛋白和低血清转铁蛋白水平的报道促使研究人员将铁代谢失调视为ALS病理生理学的一个组成部分。然而，由于所研究模型和铁标志物的多样性，包括所有研究之间缺乏共识，提出一个通用机制似乎很复杂。关于临床研究报告，大多数报告没有考虑炎症、肾功能不全和营养状况等混淆因素。此外，铁调节途径，特别是涉及铁调素的途径，在ALS铁过载的发病机制中尚未得到充分探索。从这个意义上说，探索铁过载与其他ALS相关事件之间的关系也很重要，如神经炎症、蛋白质聚集和铁驱动的细胞死亡，即铁死亡。在这篇综述中，我们指出了某些研究设计的局限性，这些局限性可能会妨碍对铁在ALS中作用的理解，并讨论了已发表数据对于铁代谢失调在该疾病中的致病影响以及针对该途径的治疗方法的相关性。
