Abnormal Copper Homeostasis: Mechanisms and Roles in Neurodegeneration

Abstract

As a cofactor of proteins and enzymes involved in critical molecular pathways in mammals and low eukaryotes, copper is a transition metal essential for life. The intra-cellular and extra-cellular metabolism of copper is under tight control, in order to maintain free copper concentrations at very low levels. Copper is a critical element for major neuronal functions, and the central nervous system is a major target of disorders of copper metabolism. Both the accumulation of copper and copper deficiency are associated with brain dysfunction. The redox capacities of free copper, its ability to trigger the production of reactive oxygen species and the close relationships with the regulation of iron and zinc are remarkable features. Major advances in our understanding of the relationships between copper, neuronal functions and neurodegeneration have occurred these last two decades. The metabolism of copper and the current knowledge on the consequences of copper dysregulation on brain disorders are reviewed, with a focus on neurodegenerative diseases, such as Wilson's disease, Alzheimer's disease and Parkinson's disease. In vitro studies, in vivo experiments and evidence from clinical observations of the neurotoxic effects of copper provide the basis for future therapies targeting copper homeostasis.

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“…In-vivo studies have shown that cardiac MT prevents lethal toxicity and lipid peroxidation induced by the administration of Adriamycin. 15 But hepatic MT pre-induced with zinc failed to prevent CCl4-induced lipid peroxidation. 16 These authors concluded that it was not completely clear whether MT plays a protective role against free radicals in-vivo but induction of MT synthesis by CCl4 was independent of lipid peroxidation, free radical generation and glutathione metabolism in the liver 16 …”

“…14 An injection of peroxidative agents such as carbon tetrachloride (CCl4), paraquat and acetaminophen induced MT production in experimental mice. 15 Any condition that promotes the induction of MT is potentially capable of inducing lipid peroxidation. Other researchers have reported dissimilar functionality between MT from different origins in the body.…”

“…15 It was first described in 1948. It is the major copper-carrying protein in the blood and it exhibits a copper-dependent oxidase activity, which is associated with possible oxidation of Fe 2+ (ferrous iron) into Fe 3+ (ferric iron), therefore assisting in its transport in the plasma in association with transferrin which can only carry iron in the ferric state.…”

“…Ceruloplasmin in humans is encoded by the ceruloplasmin gene which has been mapped to chromosome 3q24. 15 It is the product of an intragenic triplication and is composed of three homologous domains with an estimated molecular weight of 151 kDa and has six or seven cupric ions per molecule. 15 Two splice variants, CP-1 and CP-2, have differential expression in specific tissues.…”

“…15 It is the product of an intragenic triplication and is composed of three homologous domains with an estimated molecular weight of 151 kDa and has six or seven cupric ions per molecule. 15 Two splice variants, CP-1 and CP-2, have differential expression in specific tissues. Ceruloplasmin mRNAs are expressed in human liver, macrophages and lymphocytes.…”