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Science (New York, N.Y.) Mar 2022Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic...
Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms.
Topics: Animals; Cell Respiration; Citric Acid Cycle; Copper; Dihydrolipoyllysine-Residue Acetyltransferase; Hepatolenticular Degeneration; Homeostasis; Humans; Hydrazines; Ionophores; Iron-Sulfur Proteins; Lipoylation; Metabolic Networks and Pathways; Mice; Mitochondria; Regulated Cell Death
PubMed: 35298263
DOI: 10.1126/science.abf0529 -
Seminars in Neurology Aug 2023Wilson's disease (WD) can present with liver disease, neurological deficits, and psychiatric disorders. Results of genetic prevalence studies suggest that WD might be...
Wilson's disease (WD) can present with liver disease, neurological deficits, and psychiatric disorders. Results of genetic prevalence studies suggest that WD might be much more common than previously estimated. Early recognition of WD remains challenging because it is a great imitator and requires a high index of suspicion for correct and timely diagnosis. Early diagnosis of WD is crucial to ensure that patients can be started on adequate treatment. In association with other clinical and biochemical tests, liver biopsy results and molecular genetic testing can also be used for diagnosing WD. Medical therapy is effective for most patients; liver transplant can rescue those with acute liver failure or those with advanced liver disease who fail to respond to or discontinue medical therapy. Although novel therapies, such as gene therapy, are on the horizon, screening and prevention of delayed diagnosis remains paramount.
Topics: Humans; Hepatolenticular Degeneration; Biopsy; Genetic Therapy; Mental Disorders
PubMed: 37607588
DOI: 10.1055/s-0043-1771465 -
International Journal of Molecular... Dec 2020Copper is one of the most abundant basic transition metals in the human body. It takes part in oxygen metabolism, collagen synthesis, and skin pigmentation, maintaining... (Review)
Review
Copper is one of the most abundant basic transition metals in the human body. It takes part in oxygen metabolism, collagen synthesis, and skin pigmentation, maintaining the integrity of blood vessels, as well as in iron homeostasis, antioxidant defense, and neurotransmitter synthesis. It may also be involved in cell signaling and may participate in modulation of membrane receptor-ligand interactions, control of kinase and related phosphatase functions, as well as many cellular pathways. Its role is also important in controlling gene expression in the nucleus. In the nervous system in particular, copper is involved in myelination, and by modulating synaptic activity as well as excitotoxic cell death and signaling cascades induced by neurotrophic factors, copper is important for various neuronal functions. Current data suggest that both excess copper levels and copper deficiency can be harmful, and careful homeostatic control is important. This knowledge opens up an important new area for potential therapeutic interventions based on copper supplementation or removal in neurodegenerative diseases including Wilson's disease (WD), Menkes disease (MD), Alzheimer's disease (AD), Parkinson's disease (PD), and others. However, much remains to be discovered, in particular, how to regulate copper homeostasis to prevent neurodegeneration, when to chelate copper, and when to supplement it.
Topics: Animals; Astrocytes; Biological Transport; Biomarkers; Brain; Copper; Disease Management; Disease Susceptibility; Hepatolenticular Degeneration; Homeostasis; Humans; Metabolic Networks and Pathways; Neurodegenerative Diseases; Neurons; Organ Specificity
PubMed: 33291628
DOI: 10.3390/ijms21239259 -
Saudi Journal of Gastroenterology :... 2022Wilson disease (WD) is an autosomal recessive disorder caused by mutations of the ATP7B gene, with a reported prevalence of 1:30,000-50,000. ATP7B encodes an enzyme... (Review)
Review
Wilson disease (WD) is an autosomal recessive disorder caused by mutations of the ATP7B gene, with a reported prevalence of 1:30,000-50,000. ATP7B encodes an enzyme called transmembrane copper-transporting ATPase, which is essential for copper incorporation into ceruloplasmin and for copper excretion into the bile. A lack or dysfunction of this enzyme results in a progressive accumulation of copper in several organs, especially in the liver, the nervous system, corneas, kidneys, and heart. Children with WD can present with asymptomatic liver disease, cirrhosis, or acute liver failure, with or without neurological and psychiatric symptoms. Approximately 20%-30% of WD patients present with ALF, while most of the other patients have chronic progressive hepatitis or cirrhosis if untreated. Although genetic testing has become a more important diagnostic tool for WD, the diagnosis remains based on both clinical features and laboratory investigations. The aims of treatment are to reduce copper levels and prevent its accumulation in the liver and other organs, especially in the central nervous system. Liver transplantation in WD is a life-saving option for patients presenting with liver failure and encephalopathy. For WD patients treated with chelating agents, adherence to the therapy is essential for long-term success. In this review, we also address specific issues in young adults as compared to children.
Topics: Child; Copper; Hepatolenticular Degeneration; Humans; Liver; Liver Transplantation; Mutation; Young Adult
PubMed: 35042319
DOI: 10.4103/sjg.sjg_501_21 -
Translational Neurodegeneration Feb 2022Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B (encoding a copper-transporting P-type ATPase) variants that shows various...
BACKGROUND
Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B (encoding a copper-transporting P-type ATPase) variants that shows various characteristics according to race and geographical region. This study was aimed to provide a comprehensive analysis of ATP7B variants in China and to investigate a plausible role of common variants in WD manifestations.
METHODS
A total of 1366 patients (1302 index patients and 64 siblings) clinically diagnosed with WD (Leipzig score ≥ 4) were recruited. They underwent ATP7B gene sequencing and information of age and symptoms at onset was collected. The genotype-phenotype correlation was assessed in the index patients who were examined with two pathogenic variants and onset with hepatic (n = 276) or neurologic (n = 665) symptoms.
RESULTS
We identified 294 potentially pathogenic ATP7B variants (112 truncating, 174 missense, 8 in-frame) in the 1302 index patients, including 116 novel variants. The most frequent variant was c.2333G>T (R778L, allele frequency: 28.96%), followed by c.2975C>T (P992L, 13.82%), c.2621C>T (A874V, 5.99%), c.2755C>G (R919G, 2.46%), and c.3646G>A (V1216M, 1.92%). In 1167 patients, both pathogentic variants were identified, of which 532 different variant combinations were found. By binary logistic regression analysis, the factor associated with neurological presentation was high age-at-onset, but not sex, protein-truncating variant (PTV), or the common missense variants (R778L, P992L, and A874V). In the neurological group, low age-at-onset was a factor associated with dystonia, gait abnormality, and salivation; high age-at-onset was a factor associated with tremor; and the sex, low age-at-onset and A874V were independent factors associated with dysarthria. In addition, PTV, R778L, and P992L were predominant in early-onset patients, whereas A874V was predominant in late-onset patients, and patients with R778L/A874V genotype displayed a higher age-at-onset than patients with R778L/R778L or R778L/P992L genotype.
CONCLUSIONS
Our work expanded the ATP7B variant spectrum and highlighted the differences among patients with WD in age-at-onset and ATP7B variants, which may provide some valuable insights into the diagnosis, counseling, and treatment of patients with WD.
Topics: China; Gene Frequency; Genetic Association Studies; Genotype; Hepatolenticular Degeneration; Humans
PubMed: 35220961
DOI: 10.1186/s40035-022-00287-0 -
Hepatology Communications Jun 2023Wilson disease (WD) is caused by autosomal variants affecting the ATP7B gene on chromosome 13, resulting in alterations in physiological copper homeostasis and copper...
Wilson disease (WD) is caused by autosomal variants affecting the ATP7B gene on chromosome 13, resulting in alterations in physiological copper homeostasis and copper accumulation. Excess copper clinically manifests in many organs, most often in the central nervous system and liver, ultimately causing cirrhosis and death. Often considered a pediatric or young adult disease, WD actually affects patients of all ages, and aging patients need to be regularly managed with long-term follow-up. Despite over a century of advances in diagnosis and treatment, WD is still associated with diagnostic challenges and considerable disability and death, in part due to delays in diagnosis and limitations in treatment. Standard-of-care treatments are considered generally effective when the diagnosis is timely but are also limited by efficacy, safety concerns, multiple daily dosing, and adherence. This expert perspective review seeks to facilitate improvements in the awareness, understanding, diagnosis, and management of WD. The objectives are to provide a full overview of WD and streamline updated diagnosis and treatment guidance, as recently published by the American Association for the Study of Liver Diseases, in a practical way for clinical use.
Topics: Humans; Child; Hepatolenticular Degeneration; Copper; Liver Cirrhosis; Homeostasis
PubMed: 37184530
DOI: 10.1097/HC9.0000000000000150 -
Gastroenterology Jun 2021Both existing clinical criteria and genetic testing have significant limitations for the diagnosis of Wilson disease (WD), often creating ambiguities in patient...
BACKGROUND & AIMS
Both existing clinical criteria and genetic testing have significant limitations for the diagnosis of Wilson disease (WD), often creating ambiguities in patient identification and leading to delayed diagnosis and ineffective management. ATP7B protein concentration, indicated by direct measurement of surrogate peptides from patient dried blood spot samples, could provide primary evidence of WD. ATP7B concentrations were measured in patient samples from diverse backgrounds, diagnostic potential is determined, and results are compared with biochemical and genetic results from individual patients.
METHODS
Two hundred and sixty-four samples from biorepositories at 3 international and 2 domestic academic centers and 150 normal controls were obtained after Institutional Review Board approval. Genetically or clinically confirmed WD patients with a Leipzig score >3 and obligate heterozygote (carriers) from affected family members were included. ATP7B peptide measurements were made by immunoaffinity enrichment mass spectrometry.
RESULTS
Two ATP7B peptides were used to measure ATP7B protein concentration. Receiver operating characteristics curve analysis generates an area under the curve of 0.98. ATP7B peptide analysis of the sequence ATP7B 887 was found to have a sensitivity of 91.2%, specificity of 98.1%, positive predictive value of 98.0%, and a negative predictive value of 91.5%. In patients with normal ceruloplasmin concentrations (>20 mg/dL), 14 of 16 (87.5%) were ATP7B-deficient. In patients without clear genetic results, 94% were ATP7B-deficient.
CONCLUSIONS
Quantification of ATP7B peptide effectively identified WD patients in 92.1% of presented cases and reduced ambiguities resulting from ceruloplasmin and genetic analysis. Clarity is brought to patients with ambiguous genetic results, significantly aiding in noninvasive diagnosis. A proposed diagnostic score and algorithm incorporating ATP7B peptide concentrations can be rapidly diagnostic and supplemental to current Leipzig scoring systems.
Topics: Adolescent; Adult; Aged; Case-Control Studies; Ceruloplasmin; Child; Child, Preschool; Copper-Transporting ATPases; Female; Genetic Testing; Hepatolenticular Degeneration; Heterozygote; Humans; Infant; Male; Mass Spectrometry; Middle Aged; Peptides; Predictive Value of Tests; ROC Curve; Sensitivity and Specificity; Young Adult
PubMed: 33640437
DOI: 10.1053/j.gastro.2021.02.052 -
Hepatology (Baltimore, Md.) Oct 2022Wilson's disease (WD) is a rare hereditary disorder due to ATP7B gene mutation, causing pathologic copper storage mainly in the liver and neurological systems....
BACKGROUND AND AIMS
Wilson's disease (WD) is a rare hereditary disorder due to ATP7B gene mutation, causing pathologic copper storage mainly in the liver and neurological systems. Hepatocyte transplantation showed therapeutic potential; however, this strategy is often hindered by a shortage of quality donor cells and by allogeneic immune rejection. In this study, we aimed to evaluate the function and efficacy of autologous reprogrammed, ATP7B gene-restored hepatocytes using a mouse model of WD.
APPROACH AND RESULTS
Sufficient liver progenitor cells (LPCs) were harvested by reprogramming hepatocytes from ATP7B mice with small molecules, which exhibited strong proliferation and hepatic differentiation capacity in vitro. After lentivirus-mediated mini ATP7B gene transfection and redifferentiation, functional LPC-ATP7B-derived hepatocytes (LPC-ATP7B-Heps) were developed. RNA sequencing data showed that, compared with LPC-green fluorescent protein-Heps (LPC-GFP-Heps) with enrichment of genes that were mainly in pathways of oxidative stress and cell apoptosis, in LPC-ATP7B-Heps under high copper stress, copper ion binding and cell proliferation pathways were enriched. LPC-ATP7B-Heps transplantation into ATP7B mice alleviated deposition of excess liver copper with its associated inflammation and fibrosis, comparable with those observed using normal primary hepatocytes at 4 months after transplantation.
CONCLUSIONS
We established a system of autologous reprogrammed WD hepatocytes and achieved ATP7B gene therapy in vitro. LPC-ATP7B-Heps transplantation demonstrated therapeutic efficacy on copper homeostasis in a mouse model of WD.
Topics: Animals; Copper; Copper-Transporting ATPases; Disease Models, Animal; Genetic Therapy; Green Fluorescent Proteins; Hematopoietic Stem Cell Transplantation; Hepatocytes; Hepatolenticular Degeneration; Mutation
PubMed: 35340061
DOI: 10.1002/hep.32484