Pathogenesis of Wilson Disease: Molecular mechanisms of ATP7B trafficking in the maintenance of copper homeostasis

In recent years, it has become clear that several genetic disorders are caused by gene mutations that disrupt the ability of gene products to reach the specific targets where they are expected to execute their function. Among these genes, ATP7B, encodes the protein with an important role in the regulation of copper (Cu) levels in the body. Newly synthesized ATP7B travels through the system of membrane organelles, that constitute the membrane secretory pathway, to its functional sites in liver cells. There it removes the excess of the dietary Cu from the body by pumping it across the membrane of the liver cell into the biliary flow. Mutations do not allow the aberrant ATP7B to move properly through the secretory pathway to the specific sites where copper transport is needed and, therefore, result in Cu accumulation in the liver. Build-up of Cu results in the development of Wilson disease that is fatal (if not treated) and is manifested through liver abnormalities, neurodegeneration and psychiatric symptoms comprising depression and psychosis. Given that the main ATP7B mutants lose their function due to strong mis-localization, the correction of their trafficking and targeting to appropriate functional sites is expected to be beneficial for the majority of Wilson disease patients. However, the question as to which mechanisms drive ATP7B transport and to which extent they are affected by ATP7B mutations remains to be answered. The aim of our project is to identify regulatory mechanisms that are involved in ATP7B localization and trafficking and to understand their importance for the development of Wilson disease. Therefore, by using the expertise and advanced technical tools available both in our laboratory and in the Institute, we intend not only to provide answers for the above questions, but also to detect molecules that can be used for the correction of ATP7B transport and, therefore, for the development of novel strategies to cure Wilson disease.