Animal models of Wilson disease

Abstract

Wilson disease (WD) is an autosomal recessive disorder of copper metabolism manifesting with hepatic, neurological and psychiatric symptoms. The limitations of the currently available therapy for WD (particularly in the management of neuropsychiatric disease), together with our limited understanding of key aspects of this illness (e.g. neurological vs. hepatic presentation) justify the ongoing need to study WD in suitable animal models. Four animal models of WD have been established: the Long-Evans Cinnamon rat, the toxic-milk mouse, the Atp7b knockout mouse and the Labrador retriever. The existing models of WD all show good similarity to human hepatic WD and have been helpful in developing an improved understanding of the human disease. As mammals, the mouse, rat and canine models also benefit from high homology to the human genome. However, important differences exist between these mammalian models and human disease, particularly the absence of a convincing neurological phenotype. This review will first provide an overview of our current knowledge of the orthologous genes encoding ATP7B and the closely related ATP7A protein in C. elegans, Drosophila and zebrafish (Danio rerio) and then summarise key characteristics of rodent and larger mammalian models of ATP7B-deficiency.

Hepatic copper accumulation in a young cat with familial variations in the ATP7B gene

“…Therefore, it was suspected that the 2 cats with the same mother had a familial disorder of copper metabolism equivalent to WD in humans. Although several animal models of WD have been identified, including the toxic milk mouse, Long‐Evans Cinnamon rat, and Labrador Retrievers, no feline models of WD have been reported. Therefore, ours is the first case report of naturally occurring WD in cats.…”

Extending the mode of action of triethylenetetramine (trientine): Autophagy besides copper chelation

“…We read the paper by Kim et al 1 with great interest. This is an elegant multicenter study with a large patient cohort comparing the efficacy of radiofrequency (RFA) to stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC).…”

“…The rationale for using TETA in WD is based on the ability of TETA to act as a mild copper chelator, reducing copper absorption in the gastrointestinal tract and favoring its elimination via feces and urine. 1,2 It has been previously demonstrated that copper overload can directly impair mitochondrial structure and dynamics, even at pre-pathological stages of the disease. 3,4 The progressive accumulation of non-disposable copper-loaded mitochondria may explain a compensatory increase in cellular autophagy (which reportedly occurs in WD hepatocytes 5 ), a pro-survival pathway that couples the bioenergetic demands of cells with the sequestration and subsequent lysosomal digestion of intracellular components.…”

Laser Ablation Inductively Coupled Plasma Spectrometry: Metal Imaging in Experimental and Clinical Wilson Disease

“…In recent years, several preclinical animal models of WD were established [10][11][12]. These models are highly helpful to test novel drugs, examine Cu distribution and metabolism, and to improve the understanding of mechanisms by which Cu exerts its toxic effects [10].…”