The Role of Glia in Wilson's Disease: Clinical, Neuroimaging, Neuropathological and Molecular Perspectives

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.

Keywords: Wilson’s disease; astrocytes; copper; cuproptosis; ferroptosis; glia; iron; neurogeneration; neuropathology; neuroprotection.

Figure 1

Symmetrical changes visualized in putamen, caudate, and thalamus with bright claustrum sign in brain MRI in T2-weighted sequences (a) and FLAIR sequences (b) (source: own material from 2nd Department of Neurology, Institute Psychiatry and Neurology, Warsaw, Poland).

Figure 2

Copper transport paths in astrocytes. Copper can be taken up into astrocytes by copper transporter receptor 1 (Ctrl) and probably also by divalent metal transporter 1 (DMT1). These transporters have been reported to prefer Cu⁺ as a substrate. Astrocyte ecto-cuprireductase and/or extracellular ascorbate may reduce Cu²⁺ for uptake. Accumulated copper is sequestered by glutathione (GSH) in astrocytes or stored in metallothioneins (MT). In addition, copper is shuttled to its specific cellular targets by the copper chaperones: copper chaperone for superoxide dismutase (CCS) to superoxide dismutase 1 (SOD1), Coxl7 to cytochrome c oxidase, and antioxidant protein 1 (Atox l) to ATP-ase 7A (ATP7A). ATP7A transports copper to the trans-Golgi network (TGN) to then bind to copper-dependent enzymes such as ceruloplasmin (CPN). When cellular copper levels rise above a certain threshold, ATP7A is reversibly translocated to the plasma membrane via vesicles. ATP7A brings copper into vesicles for release by fusion with the plasma membrane and/or exports copper directly.

Figure 3

Copper transport paths in astrocytes. A proposed model for astrocytic copper delivery to neurons. (a) In the normal brain, astrocytes efficiently take up copper via Ctr1 and other unidentified transporters. Excess copper is sequestered by glutathione (GSH) in astrocytes or stored in metallothioneins (MT), and copper is released via ATP7A to supply neurons with copper. (b) Under conditions of copper overload, excess copper is efficiently absorbed by astrocytes and stored in MT or as a GSH complex to prevent copper-induced neurotoxicity.

Figure 4

Iron transport paths in astrocytes.