Hepatolenticular Degeneration

Copper-Induced Epigenetic Changes Shape the Clinical Phenotype in Wilson’s Disease

Wilson's disease is a congenital disorder of copper metabolism whose pathogenesis remains, at least in part, unknown. Subjects carrying the same genotype may show completely different phenotypes, differing for the age at illness onset or for the hepatic, neurologic or psychiatric clinical presentation. The inability to find a unequivocal correlation between the type of mutation in the ATPase copper transporting beta (ATP7B) gene and the phenotypic manifestation, has encouraged many authors to look for epigenetic factors interacting with the genetic changes. Here, the evidences regarding the ability of copper overload to change the global DNA methylation status are discussed.

Current Drug Managements of Wilson’s Disease: From West to East

Wilson’s disease (WD), also called hepatolenticular degeneration, is an autosomal recessive inheritance disorder of copper metabolism characterized by the multiple mutations in the ATP-ase 7B gene of chromosome 13q. About half of the WD patients have neurological or psychiatric symptoms. As WD is a kind of medicable or nearly curable neurodegenerative disease in the field of medicine, early consideration/examination and without delay/ life-long treatment usually lead to better prognoses. The drugs, also named as anticopper agents, are commonly used in clinics including D-penicillamine, trientine, sodium dimercaptosuccinate, dimercaptosuccinic acid, zinc and tetrathiomolybdate. This provides detailed reviews about these medicines.

Editorial (Thematic Selection: Strategies of Current Drugs and Alternative Treatments for Neurodegenerative Diseases)

Aceruloplasminemia

Ceruloplasmin contains 95% of the copper in human serum and plays an important role in iron efflux from mammalian cells, including brain cells, due to the activity of ferroxidase, which oxidizes ferrous iron following its transfer to the cell surface via the iron transporter, ferroportin, and delivers ferric iron to extracellular transferrin. In the central nervous system, a glycosylphosphatidylinositol (GPI)-anchored ceruloplasmin bound to the cell membranes of astrocytes was found to be the major isoform of this protein. Inherited loss of the protein causes aceruloplasminemia, which is an autosomal recessive disorder characterized by progressive neurodegeneration of the retina and basal ganglia associated with specific inherited mutations in the ceruloplasmin gene. Aceruloplasminemia is classified as an inherited neurodegenerative disorder called “neurodegeneration with brain iron accumulation” (NBIA) due to genetic defects associated with iron metabolism. Clinical and pathologic studies in patients with aceruloplasminemia and ceruloplasmin knockout mice revealed increased lipid peroxidation due to iron-mediated cellular radical injury which is caused by a marked accumulation of iron in the affected parenchymal tissues such as the retina, liver, pancreas and brain. In the following review of aceruloplasminemia, the ceruloplasmin gene expression, structure and function will be presented, and the role of ceruloplasmin in iron metabolism will be discussed. The pathogenesis of aceruloplasminemia provides valuable insights into the mechanisms regulating iron homeostasis and also identified models that can be used to further dissect the role of this metal in neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases, in which iron is accumulated.

Metal Transport and Homeostasis within the Human Body: Toxicity Associated with Transport Abnormalities

In this work, latest reports about metal toxicity, transport and homeostasis have been thoroughly described and discussed. Although diseases associated with transport and homeostasis abnormalities are those of great interest, still a variety of the phenomena associated with these processes are under debate. In this paper, we try to summarize the newest theses on this topic, presenting contradictory points of view. We focus on toxic and essential metal pathways crossing and try to follow the exact metal binding molecules within the body and provide insight into the transport mechanism. Special attention is given to the mechanism of action of lately investigated metal transporters.

Evolution of Copper Transporting ATPases in Eukaryotic Organisms

Copper is an essential nutrient for most life forms, however in excess it can be harmful. The ATP-driven copper pumps (Copper-ATPases) play critical role in living organisms by maintaining appropriate copper levels in cells and tissues. These evolutionary conserved polytopic membrane proteins are present in all phyla from simplest life forms (bacteria) to highly evolved eukaryotes (Homo sapiens). The presumed early function in metal detoxification remains the main function of Copper-ATPases in prokaryotic kingdom. In eukaryotes, in addition to removing excess copper from the cell, Copper-ATPases have another equally important function - to supply copper to copper dependent enzymes within the secretory pathway. This review focuses on the origin and diversification of Copper ATPases in eukaryotic organisms. From a single Copper ATPase in protozoans, a divergence into two functionally distinct ATPases is observed with the evolutionary appearance of chordates. Among the key functional domains of Copper-ATPases, the metal-binding Nterminal domain could be responsible for functional diversification of the copper ATPases during the course of evolution.

Re-Wiring the Circuit: Mitochondria as a Pharmacological Target in Liver Disease

Mitochondria play a key role in intracellular energy-generating processes, cell life and death, and are heavily involved in several metabolic pathways by integrating signaling networks; thus, a very large number of conditions are characterized by mitochondrial bioenergetic in humans. Often, mitochondrial changes are directly or indirectly dependent on the activation of intracellular stress cascades or death receptor-mediated pathways. Reactive oxygen species (ROS) formation, glutathione (GSH) depletion, protein alkylation and respiratory complex alterations are major events associated with mitochondrial dysfunction and represent critical initiating events in most forms of chronic liver disease.

Through creating an analogy with a disrupted electric circuit gone bad, the present review focuses initially on how hepatic mitochondrial bioenergetics is affected in the context of drug and disease-induced liver failure and how targeting mitochondria with several antioxidant agents can be helpful for preventing the disruption of the mitochondrial electric circuit.

Anti-Copper Therapies in Alzheimers Disease: New Concepts

Alzheimers disease (AD) is a heterogeneous and progressive neurodegenerative disorder. The recent Metal Hypothesis states that the interaction of Amyloid beta (Aβ, the main constituent of senile plaques) with transition metals is at the basis of AD neurodegeneration. This hypothesis is based on in vitro studies demonstrating that metals (copper, zinc) accelerate the aggregation and precipitation into plaques of Aβ, ultimately leading to synaptic dysfunction and accelerated amyloidogenesis. Recently, we have identified in AD patients a specific ‘copper disease’ marker, consisting in a serumincrease of copper not bound to ceruloplasmin, named ‘free’ copper. Several patents have been issued in the recent years and many clinical trials have been attempted in search of an anti-metal effect counteracting AD progression. Some of them have delivered very encouraging results. These anti-metal agents, however, have also shown adverse events. This work is aimed at reviewing ‘old’ and ‘new’ attitudes towards the use of anti-copper complexing agents or biological molecules which induce or maintain a state of copper malabsorption, such as zinc compounds, paying special attention to how such a rethinking of ‘old’ clinical trials might trace new routes in planning ‘modern’ ones.