Wilson's disease: a comprehensive review of the molecular mechanisms

Abstract

Wilson's disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive inherited disorder resulting from abnormal copper metabolism. Reduced copper excretion causes an excessive deposition of the copper in many organs such as the liver, central nervous system (CNS), cornea, kidney, joints, and cardiac muscle where the physiological functions of the affected organs are impaired. The underlying molecular mechanisms for WD have been extensively studied. It is now believed that a defect in P-type adenosine triphosphatase (ATP7B), the gene encoding the copper transporting P-type ATPase, is responsible for hepatic copper accumulation. Deposited copper in the liver produces toxic effects via modulating several molecular pathways. WD can be a lethal disease if left untreated. A better understanding of the molecular mechanisms causing the aberrant copper deposition and organ damage is the key to developing effective management approaches.

Figure 1

Diagram of ATP7B. The metal-binding domain contains six copper-binding domains (MBD1-6), all with the conserved sequence motif CXXC. The transmembrane channel consisting of eight discontinuous ion channels may contribute to copper transport (Cylinder1-8). The Cys–Pro–Cys (CPC) sequence motif is the key residue that confers metal ion selectively. ATP binds to the N-domain and the SEHPL motif located in the N-domain. The P-domain is the room for phosphorylation of Asp from the sequence DKTGT. The A-domain is the place where the acyl-phosphate gets dephosphorylated. Mutations may occur at any position of the gene, and then may cause the deposition of copper.

Figure 2

Copper is delivered by HCTR1 to cytosol where it mainly binds to Atox1. Atox1 transfers copper to TGN and is transported into the lumen with the help of ATP7B. Copper is then incorporated into ceruloplasmin which is then released to vascellum. The excess copper facilitates ATP7B trafficking from the TGN to the lysosome, then copper can be transported to the lysosomal lumen, and the excess copper is excreted to bile via exocytosis. An increasing level of copper also stimulates ATP7B to move to cytosolic vesicles where copper is isolated and then released into the bile duct.