Department of Biomedical Sciences, Faculty of Medicine, Collegium Medicum, Cardinal Stefan Wyszynski University, Wóycickiego 1/3, 01-938 Warsaw, Poland.
Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego St., 02-106 Warsaw, Poland.
Int J Mol Sci. 2024 Jul 9;25(14):7545. doi: 10.3390/ijms25147545.
Wilson's disease (WD) is inherited in an autosomal recessive manner and is caused by pathogenic variants of the gene, which are responsible for impaired copper transport in the cell, inhibition of copper binding to apoceruloplasmin, and biliary excretion. This leads to the accumulation of copper in the tissues. Copper accumulation in the CNS leads to the neurological and psychiatric symptoms of WD. Abnormalities of copper metabolism in WD are associated with impaired iron metabolism. Both of these elements are redox active and may contribute to neuropathology. It has long been assumed that among parenchymal cells, astrocytes have the greatest impact on copper and iron homeostasis in the brain. Capillary endothelial cells are separated from the neuropil by astrocyte terminal legs, putting astrocytes in an ideal position to regulate the transport of iron and copper to other brain cells and protect them if metals breach the blood-brain barrier. Astrocytes are responsible for, among other things, maintaining extracellular ion homeostasis, modulating synaptic transmission and plasticity, obtaining metabolites, and protecting the brain against oxidative stress and toxins. However, excess copper and/or iron causes an increase in the number of astrocytes and their morphological changes observed in neuropathological studies, as well as a loss of the copper/iron storage function leading to macromolecule peroxidation and neuronal loss through apoptosis, autophagy, or cuproptosis/ferroptosis. The molecular mechanisms explaining the possible role of glia in copper- and iron-induced neurodegeneration in WD are largely understood from studies of neuropathology in Parkinson's disease and Alzheimer's disease. Understanding the mechanisms of glial involvement in neuroprotection/neurotoxicity is important for explaining the pathomechanisms of neuronal death in WD and, in the future, perhaps for developing more effective diagnostic/treatment methods.
威尔逊病（WD）以常染色体隐性方式遗传，由基因的致病变异引起，导致细胞内铜转运受损、铜与脱辅基铜蓝蛋白结合抑制和胆汁排泄抑制，从而导致铜在组织中的积累。铜在中枢神经系统中的积累导致 WD 的神经和精神症状。WD 中铜代谢异常与铁代谢异常有关。这两种元素都是氧化还原活性的，可能有助于神经病理学。长期以来，人们一直认为，在实质细胞中，星形胶质细胞对大脑中铜和铁的动态平衡有最大的影响。毛细血管内皮细胞与神经胶质细胞的终足分离，使星形胶质细胞处于调节铁和铜向其他脑细胞转运的理想位置，如果金属突破血脑屏障，就可以保护它们。星形胶质细胞负责维持细胞外离子动态平衡、调节突触传递和可塑性、获取代谢物，并保护大脑免受氧化应激和毒素的侵害。然而，过量的铜和/或铁会导致星形胶质细胞数量增加和形态学改变，这在神经病理学研究中观察到，以及铜/铁储存功能丧失，导致大分子过氧化和神经元通过细胞凋亡、自噬或铜中毒/铁中毒而丢失。从帕金森病和阿尔茨海默病的神经病理学研究中，我们对解释胶质细胞在铜和铁诱导的 WD 神经退行性变中可能作用的分子机制有了很好的理解。了解胶质细胞参与神经保护/神经毒性的机制对于解释 WD 中神经元死亡的病理机制很重要，并且将来可能有助于开发更有效的诊断/治疗方法。
