Abstract:
Wilson\'s disease (WD) is inherited in an autosomal recessive manner and is caused by pathogenic variants of the ATP7B 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.
摘要:
威尔逊病(WD)是一种常染色体隐性遗传,是由ATP7B基因的致病变异引起的。它们是细胞中铜运输受损的原因,抑制铜与空脂蓝蛋白的结合,和胆汁排泄。这导致铜在组织中的积累。铜在CNS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受损有关。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稳态的影响最大。毛细血管内皮细胞通过星形胶质细胞末端腿与神经纤维分离,将星形胶质细胞置于理想的位置,以调节铁和铜向其他脑细胞的运输,并在金属突破血脑屏障时保护它们。星形胶质细胞负责,除其他外,维持细胞外离子稳态,调节突触传递和可塑性,获得代谢物,保护大脑免受氧化应激和毒素的侵害。然而,过量的铜和/或铁导致神经病理学研究中观察到的星形胶质细胞数量及其形态变化的增加,以及铜/铁储存功能的丧失,导致大分子过氧化和神经元通过细胞凋亡而丧失,自噬,或角化/角化。解释神经胶质在铜和铁诱导的WD神经变性中的可能作用的分子机制从帕金森病和阿尔茨海默病的神经病理学研究中得到了很大的理解。了解神经胶质参与神经保护/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,在未来,也许是为了开发更有效的诊断/治疗方法。