Copper Transporter ATP7A Research Articles

Soy Isoflavones Induce Cell Death by Copper-Mediated Mechanism: Understanding Its Anticancer Properties

Cancer incidence varies around the globe, implying a relationship between food and cancer risk. Plant polyphenols are a class of secondary metabolites that have recently attracted attention as possible anticancer agents. The subclass of polyphenols, known as isoflavones, includes genistein and daidzein, which are present in soybeans and are regarded as potent chemopreventive agents. According to epidemiological studies, those who eat soy have a lower risk of developing certain cancers. Several mechanisms for the anticancer effects of isoflavones have been proposed, but none are conclusive. We show that isoflavones suppress prostate cancer cell growth by mobilizing endogenous copper. The copper-specific chelator neocuproine decreases the apoptotic potential of isoflavones, whereas the iron and zinc chelators desferroxamine mesylate and histidine do not, confirming the role of copper. Reactive oxygen species (ROS) scavengers reduce isoflavone-induced apoptosis in these cells, implying that ROS are cell death effectors. Our research also clearly shows that isoflavones interfere with the expression of the two copper transporter genes, CTR1 and ATP7A, in cancerous cells. Copper levels are widely known to be significantly raised in all malignancies, and we confirm that isoflavones can target endogenous copper, causing prooxidant signaling and, eventually, cell death. These results highlight the importance of copper dynamics within cancer cells and provide new insight into the potential of isoflavones as cancer-fighting nutraceuticals.

Heterogeneous nuclear ribonucleoprotein hnRNPA2/B1 regulates the abundance of the copper-transporter ATP7A in an isoform-dependent manner.

Copper (Cu) is an essential micronutrient with a critical role in mammalian growth and development. Imbalance of Cu causes severe diseases in humans; therefore, cellular Cu levels are tightly regulated. Major Cu-transport proteins and their cellular behavior have been characterized in detail, whereas their regulation at the mRNA level and associated factors are not well-understood. We show that the heterogeneous nuclear ribonucleoprotein hnRNPA2/B1 regulates Cu homeostasis by modulating the abundance of Cu(I)-transporter ATP7A. Downregulation of hnRNPA2/B1 in HeLa cells increases the ATP7A mRNA and protein levels and significantly decreases cellular Cu; this regulation involves the 3' UTR of ATP7A transcript. Downregulation of B1 and B1b isoforms of hnRNPA2/B1 is sufficient to elevate ATP7A, whereas overexpression of either hnRNPA2 or hnRNPB1 isoforms decreases the ATP7A mRNA levels. Concurrent decrease in hnRNPA2/B1, increase in ATP7A, and a decrease in Cu levels was observed in neuroblastoma SH-SY5Y cells during retinoic acid-induced differentiation; this effect was reversed by overexpression of B1/B1b isoforms. We conclude that hnRNPA2/B1 is a new isoform-specific negative regulator of ATP7A abundance.

Comparison of apical and basolateral Cu treatment for iron-related gene regulation during deferoxamine induced iron deficiency.

Intestinal copper transporter (Atp7a) mutant-brindled mice with systemic Cu deficiency had elevated Cu levels in enterocyte cells without any perturbation of iron-regulating genes, suggesting that blood Cu level might be important for intestinal iron homeostasis during iron deficiency (ID). We hypothesized that the blood Cu level and polarization (apical and basolateral) of enterocyte cells might be important regulators for the compensatory response on the regulation of genes in enterocyte cells during iron deficiency. We grew Caco-2 cells on a bicameral cell culture plate to mimic the human intestine system and on a regular tissue culture plate. Iron deficiency was induced by deferoxamine (DFO). The cells were treated with Cu and Cu with Fe following mRNA expressions of DMT1, FPN, TFR, and ANKRD37 were analyzed. Our main finding was that basolateral treatment of Cu significantly reduced mRNA expressions of iron-regulated genes, including DMT1, FPN, TFR, and ANKRD37, compared to DFO-treated and DFO with apical Cu-treated groups in both bicameral and regular tissue culture plates. Cu level in the basolateral side of Caco-2 cells significantly influenced the intracellular gene regulation in DFO-induced iron-deficient condition, and polarization of the cells might be important factor gene regulation in enterocyte cells.

Naringin's Prooxidant Effect on Tumor Cells: Copper's Role and Therapeutic Implications.

Plant-derived polyphenolic chemicals are important components of human nutrition and have been found to have chemotherapeutic effects against a variety of cancers. Several studies in animal models have proven polyphenols' potential to promote apoptosis and tumor regression. However, the method by which polyphenols show their anticancer effects on malignant cells is not well understood. It is generally known that cellular copper rises within malignant cells and in the serum of cancer patients. In this communication, investigations reveal that naringin (a polyphenol found in citrus fruits) can strongly suppress cell proliferation and trigger apoptosis in various cancer cell lines in the presence of copper ions. The cuprous chelator neocuproine, which confirms copper-mediated DNA damage, prevents such cell death to a large extent. The studies further show that the cellular copper transporters CTR1 and ATP7A have a role in the survival dynamics of malignant cells after naringin exposure. The findings emphasize the crucial function of copper dynamics and mobilization in cancer cells and pave the path for a better understanding of polyphenols as nutraceutical supplements for cancer prevention and treatment.

Curcumin and Its Derivatives Induce Apoptosis in Human Cancer Cells by Mobilizing and Redox Cycling Genomic Copper Ions.

Turmeric spice contains curcuminoids, which are polyphenolic compounds found in the Curcuma longa plant's rhizome. This class of molecules includes curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Using prostate cancer cell lines PC3, LNCaP, DU145, and C42B, we show that curcuminoids inhibit cell proliferation (measured by MTT assay) and induce apoptosis-like cell death (measured by DNA/histone ELISA). A copper chelator (neocuproine) and reactive oxygen species scavengers (thiourea for hydroxyl radical, superoxide dismutase for superoxide anion, and catalase for hydrogen peroxide) significantly inhibit this reaction, thus demonstrating that intracellular copper reacts with curcuminoids in cancer cells to cause DNA damage via ROS generation. We further show that copper-supplemented media sensitize normal breast epithelial cells (MCF-10A) to curcumin-mediated growth inhibition, as determined by decreased cell proliferation. Copper supplementation results in increased expression of copper transporters CTR1 and ATP7A in MCF-10A cells, which is attenuated by the addition of curcumin in the medium. We propose that the copper-mediated, ROS-induced mechanism of selective cell death of cancer cells may in part explain the anticancer effects of curcuminoids.

Decreased Expression of the Slc31a1 Gene and Cytoplasmic Relocalization of Membrane CTR1 Protein in Renal Epithelial Cells: A Potent Protective Mechanism against Copper Nephrotoxicity in a Mouse Model of Menkes Disease.

Kidneys play an especial role in copper redistribution in the organism. The epithelial cells of proximal tubules perform the functions of both copper uptake from the primary urine and release to the blood. These cells are equipped on their apical and basal membrane with copper transporters CTR1 and ATP7A. Mosaic mutant mice displaying a functional dysfunction of ATP7A are an established model of Menkes disease. These mice exhibit systemic copper deficiency despite renal copper overload, enhanced by copper therapy, which is indispensable for their life span extension. The aim of this study was to analyze the expression of Slc31a1 and Slc31a2 genes (encoding CTR1/CTR2 proteins) and the cellular localization of the CTR1 protein in suckling, young and adult mosaic mutants. Our results indicate that in the kidney of both intact and copper-injected 14-day-old mutants showing high renal copper content, CTR1 mRNA level is not up-regulated compared to wild-type mice given a copper injection. The expression of the Slc31a1 gene in 45-day-old mice is even reduced compared with intact wild-type animals. In suckling and young copper-injected mutants, the CTR1 protein is relocalized from the apical membrane to the cytoplasm of epithelial cells of proximal tubules, the process which prevents copper transport from the primary urine and, thus, protects cells against copper toxicity.

Pomegranate juice anthocyanidins induce cell death in human cancer cells by mobilizing intracellular copper ions and producing reactive oxygen species.

Anthocyanidins are the most abundant polyphenols in pomegranate juice. This class of molecules includes Delphinidin (Del), Cyanidin (Cya), and Pelargonidin (Pel). Using prostate, breast and pancreatic cancer cell lines PC3, MDA-MB-231, BxPC-3 and MiaPaCa-2, we show that anthocyanidins inhibit cell proliferation (measured by MTT assay) and induce apoptosis like cell death (measured by DNA/Histone ELISA). Copper chelator neocuproine and reactive oxygen species scavengers (thiourea for hydroxyl radical and superoxide dismutase for superoxide anion) significantly inhibit this reaction thus demonstrating that intracellular copper reacts with anthocyanidins in cancer cells to cause DNA damage via ROS generation. We further show that copper-supplemented media sensitizes normal breast epithelial cells (MCF-10A) to Del-mediated growth inhibition as determined by decreased cell proliferation. Copper supplementation results in increased expression of copper transporters Ctr1 and ATP7A in MCF-10A cells, which is attenuated by the addition of Del in the medium. We propose that the copper mediated, ROS-induced mechanism of selective cell death of cancer cells may in part explain the anticancer effects of anthocyanidins.

A Hollow Amorphous Bimetal Organic Framework for Synergistic Cuproptosis/Ferroptosis/Apoptosis Anticancer Therapy via Disrupting Intracellular Redox Homeostasis and Copper/Iron Metabolisms

AbstractCuproptosis is a very newly recognized regulated cell death modality that is distinct from known death mechanisms and shows enormous prospect in cancer treatment. However, its efficacy is copper‐dependent and restricted by strictly regulated copper metabolism. Herein, a novel copper/iron hybrid hollow amorphous metal organic framework (HaMOF) is developed as an oxidative stress amplifier and copper/iron metabolic disrupter for synergistic cuproptosis/ferroptosis/apoptosis anticancer therapy. The HaMOF is fabricated from Cu2+, 3,3′‐dithiobis(propionohydrazide) and Fe3+ via an unsaturated coordination‐etching integration strategy, and then doxorubicin is loaded followed by surface decoration with hyaluronan. The obtained DOX@Fe/CuTH exhibits tumor microenvironment‐triggered catalytic therapeutic property, wherein it can amplify cellular oxidative stress by simultaneously boosting H2O2 production and depleting glutathione. Moreover, it can cause mitochondrial dysfunction and downregulate the expressions of copper transporter ATP7A and iron transporter FPN 1, thereby leading to metabolic disorders and high retentions of copper/iron in cytoplasm for •OH generation. The overloaded Cu2+ can cause lipoylated protein dihydrolipoamide S‐acetyltransferase aggregation and lead to cellular cuproptosis. Collectively, both augmented oxidative stress and overloaded copper/iron induce potent ferroptosis, which synergizes with cuproptosis and DOX‐mediated apoptosis to efficiently suppress tumor growth. This bimetallic hollow nanoplatform provides a new therapeutic modality paradigm to boost cuproptosis‐related therapies.

Oral Elesclomol Treatment Alleviates Copper Deficiency in Animal Models.

Copper (Cu) is an essential trace element for key biochemical reactions. Dietary or genetic copper deficiencies are associated with anemia, cardiomyopathy, and neurodegeneration. The essential requirement for copper in humans is illustrated by Menkes disease, a fatal neurodegenerative disorder of early childhood caused by mutations in the ATP7A copper transporter. Recent groundbreaking studies have demonstrated that a copper delivery small molecule compound, elesclomol (ES), is able to substantially ameliorate pathology and lethality in a mouse model of Menkes disease when injected as an ES-Cu2+ complex. It is well appreciated that drugs administered through oral means are more convenient with better efficacy than injection methods. Here we show, using genetic models of copper-deficient C. elegans and mice, that dietary ES supplementation fully rescues copper deficiency phenotypes. Worms lacking either the homolog of the CTR1 copper importer or the ATP7 copper exporter showed normal development when fed ES. Oral gavage with ES rescued intestine-specific Ctr1 knockout mice from early postnatal lethality without additional copper supplementation. Our findings reveal that ES facilitates copper delivery from dietary sources independent of the intestinal copper transporter CTR1 and provide insight into oral administration of ES as an optimal therapeutic for Menkes disease and possibly other disorders of copper insufficiency.

Structure of Some Green Tea Catechins and the Availability of Intracellular Copper Influence Their Ability to Cause Selective Oxidative DNA Damage in Malignant Cells.

The possible roles of elevated endogenous copper levels in malignant cells are becoming increasingly understood at a greater depth. Our laboratory has previously demonstrated that tea catechins have the ability to mobilize endogenous copper and undergo a Fenton-like reaction that can selectively damage cancer cells. In this communication, by using a diverse panel of malignant cell lines, we demonstrate that the ability of the catechin family [(−)-epigallocatechin-3-gallate (EGCG), (−)-epigallocatechin (EGC), (−)-epicatechin (EC), and (+)-catechin (C)] to induce apoptosis is dependent on their structure. We further confirm that reactive oxygen species (ROS) are the terminal effectors causing copper-mediated DNA damage. Our studies demonstrate the role of cellular copper transporters CTR1 and ATP7A in the survival dynamics of malignant cells post-EGCG exposure. The results, when considered together with our previous studies, highlight the critical role that copper dynamics and mobilization plays in cancer cells and paves the way for a better understanding of catechins as nutraceutical supplements for malignancies.

Copper Transporter ATP7A Promotes Myogenesis and Skeletal Muscle Regeneration in Response to Injury

Copper Transporter ATP7A Promotes Myogenesis and Skeletal Muscle Regeneration in Response to Injury

At sixes and sevens: cryptic domain in the metal binding chain of the human copper transporter ATP7A

ATP7A and ATP7B are structurally similar but functionally distinct active copper transporters that regulate copper levels in the human cells and deliver copper to the biosynthetic pathways. Both proteins have a chain of six cytosolic metal-binding domains (MBDs) believed to be involved in the copper-dependent regulation of the activity and intracellular localization of these enzymes. Although all the MBDs are quite similar in structure, their spacing differs markedly between ATP7A and ATP7B. We show by NMR that the long polypeptide between MBD1 and MBD2 of ATP7A forms an additional seventh metastable domain, which we called HMA1A (heavy metal associated domain 1A). The structure of HMA1A resembles the MBDs but contains no copper-binding site. The HMA1A domain, which is unique to ATP7A, may modulate regulatory interactions between MBD1–3, contributing to the distinct functional properties of ATP7A and ATP7B.

The P-type ATPase transporter ATP7A promotes angiogenesis by limiting autophagic degradation of VEGFR2

VEGFR2 (KDR/Flk1) signaling in endothelial cells (ECs) plays a central role in angiogenesis. The P-type ATPase transporter ATP7A regulates copper homeostasis, and its role in VEGFR2 signaling and angiogenesis is entirely unknown. Here, we describe the unexpected crosstalk between the Copper transporter ATP7A, autophagy, and VEGFR2 degradation. The functional significance of this Copper transporter was demonstrated by the finding that inducible EC-specific ATP7A deficient mice or ATP7A-dysfunctional ATP7Amut mice showed impaired post-ischemic neovascularization. In ECs, loss of ATP7A inhibited VEGF-induced VEGFR2 signaling and angiogenic responses, in part by promoting ligand-induced VEGFR2 protein degradation. Mechanistically, VEGF stimulated ATP7A translocation from the trans-Golgi network to the plasma membrane where it bound to VEGFR2, which prevented autophagy-mediated lysosomal VEGFR2 degradation by inhibiting autophagic cargo/adapter p62/SQSTM1 binding to ubiquitinated VEGFR2. Enhanced autophagy flux due to ATP7A dysfunction in vivo was confirmed by autophagy reporter CAG-ATP7Amut -RFP-EGFP-LC3 transgenic mice. In summary, our study uncovers a novel function of ATP7A to limit autophagy-mediated degradation of VEGFR2, thereby promoting VEGFR2 signaling and angiogenesis, which restores perfusion recovery and neovascularization. Thus, endothelial ATP7A is identified as a potential therapeutic target for treatment of ischemic cardiovascular diseases.

Cortical copper transporter expression in schizophrenia: interactions of risk gene dysbindin-1.

Schizophrenia susceptibility factor dysbindin-1 is associated with cognitive processes. Downregulated dysbindin-1 expression is associated with lower expression of copper transporters ATP7A and CTR1, required for copper transport to the central nervous system. We measured dysbindin-1 isoforms-1A and -1BC, CTR1, and ATP7A via Western blots of the postmortem dorsolateral prefrontal cortex (DLPFC) of schizophrenia subjects (n = 28) and matched controls (n = 14). In addition, we subdivided the schizophrenia group by treatment status and comorbidity of alcohol use disorder (AUD) and assessed the relationships between proteins. Schizophrenia subjects exhibited similar protein levels to that of controls, with no effect of antipsychotic treatment. We observed a shift towards more dysbindin-1A expression in schizophrenia, as revealed by the ratio of dysbindin-1 isoforms. Dysbindin-1A expression was negatively correlated with ATP7A in schizophrenia, with no correlation present in controls. AUD subjects exhibited less dysbindin-1BC and CTR1 than those without AUD. Our results, taken together with previous data, suggest that alterations in dysbindin-1 and copper transporters are brain-region specific. For example, protein levels of ATP7A, dysbindin 1BC, and CTR1 are lower in the substantia nigra in schizophrenia subjects. AUD in the DLPFC was associated with lower protein levels of dysbindin-1 and CTR1. Changes in dysbindin-1 isoform ratio and relationships appear to be prevalent in the disease, potentially impacting symptomology.

Markers of copper transport in the cingulum bundle in schizophrenia

Imaging and postmortem studies indicate that schizophrenia subjects exhibit abnormal connectivity in several white matter tracts, including the cingulum bundle. Copper chelators given to experimental animals damage myelin and myelin-producing oligodendrocytes, and the substantia nigra of schizophrenia subjects shows lower levels of copper, copper transporters, and copper-utilizing enzymes. This study aimed to elucidate the potential role of copper homeostasis in white matter pathology in schizophrenia.Protein levels of the copper transporters ATP7A and CTR1, and dysbindin-1, an upstream modulator of copper metabolism and schizophrenia susceptibility factor, were measured using Western blot analyses of the postmortem cingulum bundle of schizophrenia subjects (n=16) and matched controls (n=13). Additionally, the patient group was subdivided by treatment status: off- (n=8) or on-medication (n=8). Relationships between proteins from the current study were correlated among themselves and markers of axonal integrity previously measured in the same cohort.Schizophrenia subjects exhibited similar protein levels to controls, with no effect of antipsychotic treatment. The dysbindin-1A/1BC relationship was positive in controls and schizophrenia subjects; however, antipsychotic treatment appeared to reverse this relationship in a statistically different manner from that of controls and unmedicated subjects. The relationships between dysbindin-1A/neurofilament heavy and ATP7A/α-tubulin were positively correlated in the schizophrenia group that was significantly different from the lack of correlation in controls.Copper transporters and dysbindin-1 appear to be more significantly affected in the grey matter of schizophrenia subjects. However, the relationships among proteins in white matter may be more substantial and dependent on treatment status.

Regulation of murine copper homeostasis by members of the COMMD protein family.

ABSTRACTCopper is an essential transition metal for all eukaryotes. In mammals, intestinal copper absorption is mediated by the ATP7A copper transporter, whereas copper excretion occurs predominantly through the biliary route and is mediated by the paralog ATP7B. Both transporters have been shown to be recycled actively between the endosomal network and the plasma membrane by a molecular machinery known as the COMMD/CCDC22/CCDC93 or CCC complex. In fact, mutations in COMMD1 can lead to impaired biliary copper excretion and liver pathology in dogs and in mice with liver-specific Commd1 deficiency, recapitulating aspects of this phenotype. Nonetheless, the role of the CCC complex in intestinal copper absorption in vivo has not been studied, and the potential redundancy of various COMMD family members has not been tested. In this study, we examined copper homeostasis in enterocyte-specific and hepatocyte-specific COMMD gene-deficient mice. We found that, in contrast to effects in cell lines in culture, COMMD protein deficiency induced minimal changes in ATP7A in enterocytes and did not lead to altered copper levels under low- or high-copper diets, suggesting that regulation of ATP7A in enterocytes is not of physiological consequence. By contrast, deficiency of any of three COMMD genes (Commd1, Commd6 or Commd9) resulted in hepatic copper accumulation under high-copper diets. We found that each of these deficiencies caused destabilization of the entire CCC complex and suggest that this might explain their shared phenotype. Overall, we conclude that the CCC complex plays an important role in ATP7B endosomal recycling and function.

The M1311V variant of ATP7A is associated with impaired trafficking and copper homeostasis in models of motor neuron disease

Disruption in copper homeostasis causes a number of cognitive and motor deficits. Wilson's disease and Menkes disease are neurodevelopmental disorders resulting from mutations in the copper transporters ATP7A and ATP7B, with ATP7A mutations also causing occipital horn syndrome, and distal motor neuropathy. A 65 year old male presenting with brachial amyotrophic diplegia and diagnosed with amyotrophic lateral sclerosis (ALS) was found to harbor a p.Met1311Val (M1311V) substitution variant in ATP7A. ALS is a fatal neurodegenerative disease associated with progressive muscle weakness, synaptic deficits and degeneration of upper and lower motor neurons. To investigate the potential contribution of the ATP7AM1311V variant to neurodegeneration, we obtained and characterized both patient-derived fibroblasts and patient-derived induced pluripotent stem cells differentiated into motor neurons (iPSC-MNs), and compared them to control cell lines. We found reduced localization of ATP7AM1311V to the trans-Golgi network (TGN) at basal copper levels in patient-derived fibroblasts and iPSC-MNs. In addition, redistribution of ATP7AM1311V out of the TGN in response to increased extracellular copper was defective in patient fibroblasts. This manifested in enhanced intracellular copper accumulation and reduced survival of ATP7AM1311V fibroblasts. iPSC-MNs harboring the ATP7AM1311V variant showed decreased dendritic complexity, aberrant spontaneous firing, and decreased survival. Finally, expression of the ATP7AM1311V variant in Drosophila motor neurons resulted in motor deficits. Apilimod, a drug that targets vesicular transport and recently shown to enhance survival of C9orf72-ALS/FTD iPSC-MNs, also increased survival of ATP7AM1311V iPSC-MNs and reduced motor deficits in Drosophila expressing ATP7AM1311V. Taken together, these observations suggest that ATP7AM1311V negatively impacts its role as a copper transporter and impairs several aspects of motor neuron function and morphology.

Insulin-promoted mobilization of GLUT4 from a perinuclear storage site requires RAB10.

Insulin controls glucose uptake into muscle and fat cells by inducing a net redistribution of glucose transporter 4 (GLUT4) from intracellular storage to the plasma membrane (PM). The TBC1D4-RAB10 signaling module is required for insulin-stimulated GLUT4 translocation to the PM, although where it intersects GLUT4 traffic was unknown. Here we demonstrate that TBC1D4-RAB10 functions to control GLUT4 mobilization from a trans-Golgi network (TGN) storage compartment, establishing that insulin, in addition to regulating the PM proximal effects of GLUT4-containing vesicles docking to and fusion with the PM, also directly regulates the behavior of GLUT4 deeper within the cell. We also show that GLUT4 is retained in an element/domain of the TGN from which newly synthesized lysosomal proteins are targeted to the late endosomes and the ATP7A copper transporter is translocated to the PM by elevated copper. Insulin does not mobilize ATP7A nor does copper mobilize GLUT4, and RAB10 is not required for copper-elicited ATP7A mobilization. Consequently, GLUT4 intracellular sequestration and mobilization by insulin is achieved, in part, through utilizing a region of the TGN devoted to specialized cargo transport in general rather than being specific for GLUT4. Our results define the GLUT4-containing region of the TGN as a sorting and storage site from which different cargo are mobilized by distinct signals through unique molecular machinery.

HEREDITARY NEUROPATHIES & ALS: P.109 Expanding the phenotype of ATP7A-related copper transport diseases: Understanding the pathophysiology of neuropathy and copper metabolism

Genetic disorders related to ATP7A copper transporter includes classical Menkes disease (MD) and its milder form occipital horn syndrome (OHS), and ATP7A-related distal motor neuropathy (DMN). The DMN phenotype was recently described and is thought to be a distinct and clinical isolate phenotype of ATP7A related disorders, with different pathophysiology of MD and OHS. We describe clinical, biochemical, radiological characteristics and functional studies in fibroblast of two patients with a novel ATP7Agene mutation. Two related patients, nephew (patient 1) and uncle (patient 2) with the diagnosis of OHS. Patient 2 presents clinical manifestations of OHS and DMN and worsening of the neuropathy after copper treatment and functional motor recovery after a few weeks of treatment withdrawal. Genetic studies: The patients are hemizygous for c.4236delA (p.K1412NFsX15) in the exon 23 of the ATP7Agene (NM_000052.4). Pathogenic mutations of neuropathies-related genes were ruled out in a genetic panel. Mutations in the ATP7Agene presenting with the association of motor distal neuropathy and clinical features of MD or OHS have not been reported previously. It has been hypothesized that the ATP7A mutations leading to DNM may have a different impact on the function of the protein than those mutations causing MD or OHS phenotype. Further studies in the evaluation of the biological mechanisms of this novel mutation could contribute to a better understanding of the complex pathophysiology of ATP7A related disorders. Supplementation with copper-histidinate seems plausible when plasma copper is low, however, exogenous copper could be also dangerous and lead to cellular intoxication. Treatment with copper-histidinate in patients with OHS and DMN should be cautiously considered and monitored, since different repercussion of mutations in ATPA7 function may determine the copper treatment effect.

Interactions between knockout of schizophrenia risk factor Dysbindin-1 and copper metabolism in mice

Background and PurposeDTNBP1 gene variation and lower dysbindin-1 protein are associated with schizophrenia. Previous evidence suggests that downregulated dysbindin-1 expression results in lower expression of copper transporters ATP7A (intracellular copper transporter) and SLC31A1 (CTR1; extracellular copper transporter), which are required for copper transport across the blood brain barrier. However, whether antipsychotic medications used for schizophrenia treatment may modulate these systems is unclear. Experimental ApproachThe current study measured behavioral indices of neurological function in dysbindin-1 functional knockout (KO) mice and their wild-type (WT) littermates with or without quetiapine treatment. We assessed serum and brain copper levels, ATP7A and CTR1 mRNA, and copper transporter-expressing cellular population transcripts: TTR (transthyretin; choroid plexus epithelial cells), MBP (myelin basic protein; oligodendrocytes), and GJA1 (gap-junction protein alpha-1; astrocytes) in cortex and hippocampus. Key ResultsRegardless of genotype, quetiapine significantly reduced TTR, MBP, CTR1 mRNA, and serum copper levels. Neurological function of untreated KO mice was abnormal, and ledge instability was rescued with quetiapine. KO mice were hyperactive after 10 min in the open-field assay, which was not affected by treatment. Conclusions and ImplicationsDysbindin-1 KO results in hyperactivity, altered serum copper, and neurological impairment, the last of which is selectively rescued with quetiapine. Antipsychotic treatment modulates specific cellular populations, affecting myelin, the choroid plexus, and copper transport across the blood brain barrier. Together these results indicate the widespread impact of antipsychotic treatment, and that alteration of dysbindin-1 may be sufficient, but not necessary, for specific schizophrenia pathology.