| الوصف: |
Copper is an essential element for living organisms, yet it is very toxic when present in amounts exceeding cellular needs. Delicate mechanisms have evolved to ensure proper copper homeostasis is maintained for the organism, as well as at a cellular level, and perturbations in these mechanisms give rise to several severe diseases of copper homeostasis. However, the exact mechanisms through which such disorders of copper homeostasis develop are not completely understood. Therefore, the work in this thesis entitled "Novel insights in the molecular pathogenesis of human copper homeostasis disorders through studies of protein-protein interactions" aims to dissect the molecular pathogenesis of human copper homeostasis disorders. Copper deficiency, as caused by mutations in ATP7A in Menkes disease, manifests with neurological degeneration, growth defects and several other symptoms that directly relate to dysfunction of copper-dependent enzymes. Copper overload is observed in several different disorders in man. Wilson disease, for example, is caused by mutations in ATP7B and manifests with copper accumulation in the liver and brain, resulting in extensive hepatic and neurological defects. Other copper overload disorders comprise Indian childhood cirrhosis (ICC), endemic infantile Tyrolean cirrhosis (ETIC) and idiopathic copper toxicosis (ICT), caused by both excessive copper intake and an uncharacterized genetic predisposition. Recently, we identified COMMD1 as a novel protein involved in copper homeostasis; a deletion in COMMD1 underlies the development of copper toxicosis in Bedlington terriers, a disorder that shares pathophysiological features with Wilson disease, ICC, ETIC, and ICT. The experimental work in this thesis aimed to functionally characterize COMMD1 through the study of protein-protein interactions. Identifying novel interacting partners was expected to result in increased understanding of the mechanism through which COMMD1 exerts its function in copper homeostasis, and lead to identification of novel candidate genes for ICC, ETIC and ICT. Our studies resulted in the identification of the previously uncharacterized protein COMMD6 as interacting partner of COMMD1. This work has contributed to the identification and characterization of the COMMD protein family, a family consisting of nine human homologues of COMMD1. A number of COMMD proteins, including COMMD1, interact with the copper transporting ATPases ATP7A and/or ATP7B, suggesting that the COMMD protein family plays a role in copper homeostasis. Three of these COMMD proteins interact with ATP7B, implicating that they function in the hepatic copper excretion pathways. The genes encoding these COMMD proteins were investigated as candidate genes for ICC, ETIC, and ICT, revealing several single nucleotide polymorphisms that could be involved in the pathogenesis of these disorders. In addition, we observed a deregulation of the interaction between COMMD1 and ATP7B resulting from Wilson disease causing mutations in ATP7B, implicating COMMD1 in the molecular pathogenesis of Wilson disease. Further characterization of these mutations in ATP7B, resulted in our observation that COMMD1 exerts its role in ATP7B-mediated hepatic copper excretion by facilitating the degradation of ATP7B. Taken together, the research described in this thesis implicates COMMD proteins as a novel protein family in the regulation of copper transport pathways, and the pathogenesis of human copper homeostasis disorders. |
