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Ganaraja VH, Holla VV, Pal PK. Current Management of Neurological Wilson's Disease. Tremor Other Hyperkinet Mov (N Y) 2025; 15:17. [PMID: 40351566 PMCID: PMC12063596 DOI: 10.5334/tohm.938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Accepted: 02/03/2025] [Indexed: 05/14/2025] Open
Abstract
Wilson's disease (WD) is a disorder of copper metabolism due to variants in the ATP7B gene. This autosomal recessively inherited disorder is characterized by the accumulation of copper in various body parts, mainly the liver, brain, and kidneys. Initially, WD was described to involve the hepatic and neurological systems. Subsequently, diverse presentations have been reported with skeletal and hematological manifestations and various constellations of symptoms. Neurological manifestations of WD are varied, ranging from asymptomatic neurological state to refractory dystonia. Earlier, the diagnosis was based only on measuring serum ceruloplasmin levels, urinary copper levels, and imaging. Advanced genetic testing has provided an additional mode of diagnosis in the patient, screening of the family members and, a way to better understand the genotype-phenotype associations of the disease if there are any. In the last few decades, the treatment of WD has evolved from symptomatic treatment and chelation therapy to many new advanced measures for both copper chelation and symptomatic relief. With a better understanding of the genetic aspects of WD in recent years, there has been more focus on gene therapy, novel therapies targeting ATP7B genes, and therapies targeting mutant proteins to prevent copper accumulation. This article highlights the advances in diagnostic methods and treatment modalities in WD.
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Affiliation(s)
- V. H. Ganaraja
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bengaluru, India-560029
| | - Vikram V. Holla
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bengaluru, India-560029
| | - Pramod Kumar Pal
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bengaluru, India-560029
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Richa, Kumar V, Kataria R. Phenanthroline and Schiff Base associated Cu(II)-coordinated compounds containing N, O as donor atoms for potent anticancer activity. J Inorg Biochem 2024; 251:112440. [PMID: 38065049 DOI: 10.1016/j.jinorgbio.2023.112440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 11/21/2023] [Accepted: 11/22/2023] [Indexed: 12/25/2023]
Abstract
As an inherent metal ion, copper has been the subject of investigation for developing a novel antitumoral compound that exhibits fewer adverse effects. Copper serves as a cofactor in multiple enzymes, generates reactive oxygen species (ROS), facilitates tumour evolution, metastasis and angiogenesis and has been detected at elevated concentrations in the serum and tissues of various human cancer types. In the given setting, utilising two methodologies in developing novel Copper-based pharmaceuticals for anti-cancer applications is standard practice. These approaches involve either the sequestration of unbound Copper ions or the synthesis of Copper complexes that induce cellular apoptosis. In the past four decades, the latter system has been used, leading to numerous reviews that have examined the anticancer characteristics of a wide range of Copper complexes. These analyses have consistently demonstrated that multiple factors frequently influence the efficacy of these compounds. This review examines the possible anticancer properties of copper and Cu(II) complexes that incorporate Schiff base ligands containing 1,10-phenanthroline. The present study will comprehensively analyse the examined cell lines and mechanistic research associated with each complex.
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Affiliation(s)
- Richa
- Department of Chemistry & Centre for Advanced Studies in Chemistry, Panjab University, Chandigarh 160014, India
| | - Vinod Kumar
- Department of Chemistry, School of Basic Sciences, Central University of Haryana, Mahendergarh 123031, Haryana, India
| | - Ramesh Kataria
- Department of Chemistry & Centre for Advanced Studies in Chemistry, Panjab University, Chandigarh 160014, India.
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Heinken A, El Kouche S, Guéant-Rodriguez RM, Guéant JL. Towards personalized genome-scale modeling of inborn errors of metabolism for systems medicine applications. Metabolism 2024; 150:155738. [PMID: 37981189 DOI: 10.1016/j.metabol.2023.155738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 11/09/2023] [Accepted: 11/12/2023] [Indexed: 11/21/2023]
Abstract
Inborn errors of metabolism (IEMs) are a group of more than 1000 inherited diseases that are individually rare but have a cumulative global prevalence of 50 per 100,000 births. Recently, it has been recognized that like common diseases, patients with rare diseases can greatly vary in the manifestation and severity of symptoms. Here, we review omics-driven approaches that enable an integrated, holistic view of metabolic phenotypes in IEM patients. We focus on applications of Constraint-based Reconstruction and Analysis (COBRA), a widely used mechanistic systems biology approach, to model the effects of inherited diseases. Moreover, we review evidence that the gut microbiome is also altered in rare diseases. Finally, we outline an approach using personalized metabolic models of IEM patients for the prediction of biomarkers and tailored therapeutic or dietary interventions. Such applications could pave the way towards personalized medicine not just for common, but also for rare diseases.
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Affiliation(s)
- Almut Heinken
- Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy F-54000, France.
| | - Sandra El Kouche
- Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy F-54000, France
| | - Rosa-Maria Guéant-Rodriguez
- Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy F-54000, France; National Center of Inborn Errors of Metabolism, University Regional Hospital Center of Nancy, Nancy F-54000, France
| | - Jean-Louis Guéant
- Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy F-54000, France; National Center of Inborn Errors of Metabolism, University Regional Hospital Center of Nancy, Nancy F-54000, France
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Catalano F, O’Brien TJ, Mekhova AA, Sepe LV, Elia M, De Cegli R, Gallotta I, Santonicola P, Zampi G, Ilyechova EY, Romanov AA, Samuseva PD, Salzano J, Petruzzelli R, Polishchuk EV, Indrieri A, Kim BE, Brown AEX, Puchkova LV, Di Schiavi E, Polishchuk RS. A new Caenorhabditis elegans model to study copper toxicity in Wilson disease. Traffic 2024; 25:e12920. [PMID: 37886910 PMCID: PMC10841361 DOI: 10.1111/tra.12920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 09/28/2023] [Accepted: 10/03/2023] [Indexed: 10/28/2023]
Abstract
Wilson disease (WD) is caused by mutations in the ATP7B gene that encodes a copper (Cu) transporting ATPase whose trafficking from the Golgi to endo-lysosomal compartments drives sequestration of excess Cu and its further excretion from hepatocytes into the bile. Loss of ATP7B function leads to toxic Cu overload in the liver and subsequently in the brain, causing fatal hepatic and neurological abnormalities. The limitations of existing WD therapies call for the development of new therapeutic approaches, which require an amenable animal model system for screening and validation of drugs and molecular targets. To achieve this objective, we generated a mutant Caenorhabditis elegans strain with a substitution of a conserved histidine (H828Q) in the ATP7B ortholog cua-1 corresponding to the most common ATP7B variant (H1069Q) that causes WD. cua-1 mutant animals exhibited very poor resistance to Cu compared to the wild-type strain. This manifested in a strong delay in larval development, a shorter lifespan, impaired motility, oxidative stress pathway activation, and mitochondrial damage. In addition, morphological analysis revealed several neuronal abnormalities in cua-1 mutant animals exposed to Cu. Further investigation suggested that mutant CUA-1 is retained and degraded in the endoplasmic reticulum, similarly to human ATP7B-H1069Q. As a consequence, the mutant protein does not allow animals to counteract Cu toxicity. Notably, pharmacological correctors of ATP7B-H1069Q reduced Cu toxicity in cua-1 mutants indicating that similar pathogenic molecular pathways might be activated by the H/Q substitution and, therefore, targeted for rescue of ATP7B/CUA-1 function. Taken together, our findings suggest that the newly generated cua-1 mutant strain represents an excellent model for Cu toxicity studies in WD.
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Affiliation(s)
- Federico Catalano
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- Institute of Biosciences and BioResources (IBBR), National Research Council (CNR), Napoli, Italy
| | - Thomas J O’Brien
- MRC London Institute of Medical Sciences, London, United Kingdom
- Institute of Clinical Sciences, Imperial College London, London, United Kingdom
| | - Aleksandra A Mekhova
- Research center of advanced functional materials and laser communication systems, ADTS Institute, ITMO University, St. Petersburg, Russia
| | | | | | - Rossella De Cegli
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Ivan Gallotta
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- Institute of Genetics and Biophysics Adriano Buzzati-Traverso (IGB-ABT), National Research Council (CNR), Napoli, Italy
| | - Pamela Santonicola
- Institute of Biosciences and BioResources (IBBR), National Research Council (CNR), Napoli, Italy
| | - Giuseppina Zampi
- Institute of Biosciences and BioResources (IBBR), National Research Council (CNR), Napoli, Italy
| | - Ekaterina Y Ilyechova
- Research center of advanced functional materials and laser communication systems, ADTS Institute, ITMO University, St. Petersburg, Russia
- Department of Molecular Genetics, Research Institute of Experimental Medicine, St. Petersburg, Russia
| | - Aleksei A Romanov
- Department of applied mathematics, Institute of applied mathematics and mechanics, Peter the Great Polytechnic University, St. Petersburg, Russia
| | - Polina D Samuseva
- Research center of advanced functional materials and laser communication systems, ADTS Institute, ITMO University, St. Petersburg, Russia
| | - Josephine Salzano
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Raffaella Petruzzelli
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- Scuola Superiore Meridionale (SSM, School of Advanced Studies), Genomics and Experimental Medicine program, University of Naples Federico II, Naples, Italy
| | - Elena V. Polishchuk
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- Institute of Biosciences and BioResources (IBBR), National Research Council (CNR), Napoli, Italy
| | - Alessia Indrieri
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- Institute for Genetic and Biomedical Research (IRGB), National Research Council (CNR), Milan, Italy
| | - Byung-Eun Kim
- Department of Animal and Avian Sciences, University of Maryland, College Park, Maryland, USA
| | - André EX Brown
- MRC London Institute of Medical Sciences, London, United Kingdom
- Institute of Clinical Sciences, Imperial College London, London, United Kingdom
| | - Ludmila V Puchkova
- Research center of advanced functional materials and laser communication systems, ADTS Institute, ITMO University, St. Petersburg, Russia
| | - Elia Di Schiavi
- Institute of Biosciences and BioResources (IBBR), National Research Council (CNR), Napoli, Italy
- Institute of Genetics and Biophysics Adriano Buzzati-Traverso (IGB-ABT), National Research Council (CNR), Napoli, Italy
| | - Roman S. Polishchuk
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- Institute for Genetic and Biomedical Research (IRGB), National Research Council (CNR), Milan, Italy
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Wen MH, Xie X, Huang PS, Yang K, Chen TY. Crossroads between membrane trafficking machinery and copper homeostasis in the nerve system. Open Biol 2021; 11:210128. [PMID: 34847776 PMCID: PMC8633785 DOI: 10.1098/rsob.210128] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Imbalanced copper homeostasis and perturbation of membrane trafficking are two common symptoms that have been associated with the pathogenesis of neurodegenerative and neurodevelopmental diseases. Accumulating evidence from biophysical, cellular and in vivo studies suggest that membrane trafficking orchestrates both copper homeostasis and neural functions-however, a systematic review of how copper homeostasis and membrane trafficking interplays in neurons remains lacking. Here, we summarize current knowledge of the general trafficking itineraries for copper transporters and highlight several critical membrane trafficking regulators in maintaining copper homeostasis. We discuss how membrane trafficking regulators may alter copper transporter distribution in different membrane compartments to regulate intracellular copper homeostasis. Using Parkinson's disease and MEDNIK as examples, we further elaborate how misregulated trafficking regulators may interplay parallelly or synergistically with copper dyshomeostasis in devastating pathogenesis in neurodegenerative diseases. Finally, we explore multiple unsolved questions and highlight the existing challenges to understand how copper homeostasis is modulated through membrane trafficking.
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Affiliation(s)
- Meng-Hsuan Wen
- Department of Chemistry, University of Houston, Houston, TX 77204, USA
| | - Xihong Xie
- Department of Chemistry, University of Houston, Houston, TX 77204, USA
| | - Pei-San Huang
- Department of Chemistry, University of Houston, Houston, TX 77204, USA
| | - Karen Yang
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Tai-Yen Chen
- Department of Chemistry, University of Houston, Houston, TX 77204, USA
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Kasztelan-Szczerbinska B, Cichoz-Lach H. Wilson's Disease: An Update on the Diagnostic Workup and Management. J Clin Med 2021; 10:5097. [PMID: 34768617 PMCID: PMC8584493 DOI: 10.3390/jcm10215097] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 10/18/2021] [Accepted: 10/27/2021] [Indexed: 02/08/2023] Open
Abstract
Wilson's disease (WD) is a rare autosomal recessive disorder of hepatocellular copper deposition. The diagnostic approach to patients with WD may be challenging and is based on a complex set of clinical findings that derive from patient history, physical examination, as well as laboratory and imaging testing. No single examination can unequivocally confirm or exclude the disease. Timely identification of signs and symptoms using novel biomarkers and modern diagnostic tools may help to reduce treatment delays and improve patient prognosis. The proper way of approaching WD management includes, firstly, early diagnosis and prompt treatment introduction; secondly, careful and lifelong monitoring of patient compliance and strict adherence to the treatment; and, last but not least, screening for adverse effects and evaluation of treatment efficacy. Liver transplantation is performed in about 5% of WD patients who present with acute liver failure at first disease presentation or with signs of decompensation in the course of liver cirrhosis. Increasing awareness of this rare inherited disease among health professionals, emphasizing their training to consider early signs and symptoms of the illness, and strict monitoring are vital strategies for the patient safety and efficacy of WD therapy.
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Affiliation(s)
- Beata Kasztelan-Szczerbinska
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland;
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Lim JJ, Li X, Lehmler HJ, Wang D, Gu H, Cui JY. Gut Microbiome Critically Impacts PCB-induced Changes in Metabolic Fingerprints and the Hepatic Transcriptome in Mice. Toxicol Sci 2021; 177:168-187. [PMID: 32544245 DOI: 10.1093/toxsci/kfaa090] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Polychlorinated biphenyls (PCBs) are ubiquitously detected and have been linked to metabolic diseases. Gut microbiome is recognized as a critical regulator of disease susceptibility; however, little is known how PCBs and gut microbiome interact to modulate hepatic xenobiotic and intermediary metabolism. We hypothesized the gut microbiome regulates PCB-mediated changes in the metabolic fingerprints and hepatic transcriptome. Ninety-day-old female conventional and germ-free mice were orally exposed to the Fox River Mixture (synthetic PCB mixture, 6 or 30 mg/kg) or corn oil (vehicle control, 10 ml/kg), once daily for 3 consecutive days. RNA-seq was conducted in liver, and endogenous metabolites were measured in liver and serum by LC-MS. Prototypical target genes of aryl hydrocarbon receptor, pregnane X receptor, and constitutive androstane receptor were more readily upregulated by PCBs in conventional conditions, indicating PCBs, to the hepatic transcriptome, act partly through the gut microbiome. In a gut microbiome-dependent manner, xenobiotic, and steroid metabolism pathways were upregulated, whereas response to misfolded proteins-related pathways was downregulated by PCBs. At the high PCB dose, NADP, and arginine appear to interact with drug-metabolizing enzymes (ie, Cyp1-3 family), which are highly correlated with Ruminiclostridium and Roseburia, providing a novel explanation of gut-liver interaction from PCB-exposure. Utilizing the Library of Integrated Network-based Cellular Signatures L1000 database, therapeutics targeting anti-inflammatory and endoplasmic reticulum stress pathways are predicted to be remedies that can mitigate PCB toxicity. Our findings demonstrate that habitation of the gut microbiota drives PCB-mediated hepatic responses. Our study adds knowledge of physiological response differences from PCB exposure and considerations for further investigations for gut microbiome-dependent therapeutics.
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Affiliation(s)
- Joe Jongpyo Lim
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98195
| | - Xueshu Li
- Department of Occupational and Environmental Health, University of Iowa, Iowa City, Iowa 52242; and
| | - Hans-Joachim Lehmler
- Department of Occupational and Environmental Health, University of Iowa, Iowa City, Iowa 52242; and
| | - Dongfang Wang
- Arizona Metabolomics Laboratory, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Scottsdale, Arizona 85259
| | - Haiwei Gu
- Arizona Metabolomics Laboratory, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Scottsdale, Arizona 85259
| | - Julia Yue Cui
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98195
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Pharmacoproteomics pinpoints HSP70 interaction for correction of the most frequent Wilson disease-causing mutant of ATP7B. Proc Natl Acad Sci U S A 2020; 117:32453-32463. [PMID: 33288711 DOI: 10.1073/pnas.2006648117] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Pathogenic mutations in the copper transporter ATP7B have been hypothesized to affect its protein interaction landscape contributing to loss of function and, thereby, to hepatic copper toxicosis in Wilson disease. Although targeting mutant interactomes was proposed as a therapeutic strategy, druggable interactors for rescue of ATP7B mutants remain elusive. Using proteomics, we found that the frequent H1069Q substitution promotes ATP7B interaction with HSP70, thus accelerating endoplasmic reticulum (ER) degradation of the mutant protein and consequent copper accumulation in hepatic cells. This prompted us to use an HSP70 inhibitor as bait in a bioinformatics search for structurally similar Food and Drug Administration-approved drugs. Among the hits, domperidone emerged as an effective corrector that recovered trafficking and function of ATP7B-H1069Q by impairing its exposure to the HSP70 proteostatic network. Our findings suggest that HSP70-mediated degradation can be safely targeted with domperidone to rescue ER-retained ATP7B mutants and, hence, to counter the onset of Wilson disease.
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Proteostasis regulators modulate proteasomal activity and gene expression to attenuate multiple phenotypes in Fabry disease. Biochem J 2020; 477:359-380. [PMID: 31899485 PMCID: PMC6993862 DOI: 10.1042/bcj20190513] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 12/17/2019] [Accepted: 01/02/2020] [Indexed: 12/22/2022]
Abstract
The lysosomal storage disorder Fabry disease is characterized by a deficiency of the lysosomal enzyme α-Galactosidase A. The observation that missense variants in the encoding GLA gene often lead to structural destabilization, endoplasmic reticulum retention and proteasomal degradation of the misfolded, but otherwise catalytically functional enzyme has resulted in the exploration of alternative therapeutic approaches. In this context, we have investigated proteostasis regulators (PRs) for their potential to increase cellular enzyme activity, and to reduce the disease-specific accumulation of the biomarker globotriaosylsphingosine in patient-derived cell culture. The PRs also acted synergistically with the clinically approved 1-deoxygalactonojirimycine, demonstrating the potential of combination treatment in a therapeutic application. Extensive characterization of the effective PRs revealed inhibition of the proteasome and elevation of GLA gene expression as paramount effects. Further analysis of transcriptional patterns of the PRs exposed a variety of genes involved in proteostasis as potential modulators. We propose that addressing proteostasis is an effective approach to discover new therapeutic targets for diseases involving folding and trafficking-deficient protein mutants.
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Role of endoplasmic reticulum stress and protein misfolding in disorders of the liver and pancreas. Adv Med Sci 2019; 64:315-323. [PMID: 30978662 DOI: 10.1016/j.advms.2019.03.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 12/17/2018] [Accepted: 03/21/2019] [Indexed: 12/24/2022]
Abstract
The endoplasmic reticulum (ER) is the site of synthesis and folding of membrane and secretory proteins. The fraction of protein passing through the ER represents a large proportion of the total protein in the cell. Protein folding, glycosylation, sorting and transport are essential tasks of the ER and a compromised ER folding network has been recognized to be a key component in the disease pathogenicity of common neurodegenerative, metabolic and malignant diseases. On the other hand, the ER protein folding machinery also holds significant potential for therapeutic interventions. Many causes can lead to ER stress. A disturbed calcium homeostasis, the generation of reactive oxygen species (ROS) and a persistent overload of misfolded proteins within the ER can drive the course of adisease. In this review the role of ER-stress in diseases of the liver and pancreas will be examined using pancreatitis and Wilson´s disease as examples. Potential therapeutic targets in ER-stress pathways will also be discussed.
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Polishchuk EV, Merolla A, Lichtmannegger J, Romano A, Indrieri A, Ilyechova EY, Concilli M, De Cegli R, Crispino R, Mariniello M, Petruzzelli R, Ranucci G, Iorio R, Pietrocola F, Einer C, Borchard S, Zibert A, Schmidt HH, Di Schiavi E, Puchkova LV, Franco B, Kroemer G, Zischka H, Polishchuk RS. Activation of Autophagy, Observed in Liver Tissues From Patients With Wilson Disease and From ATP7B-Deficient Animals, Protects Hepatocytes From Copper-Induced Apoptosis. Gastroenterology 2019; 156:1173-1189.e5. [PMID: 30452922 DOI: 10.1053/j.gastro.2018.11.032] [Citation(s) in RCA: 159] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 10/23/2018] [Accepted: 11/10/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS Wilson disease (WD) is an inherited disorder of copper metabolism that leads to copper accumulation and toxicity in the liver and brain. It is caused by mutations in the adenosine triphosphatase copper transporting β gene (ATP7B), which encodes a protein that transports copper from hepatocytes into the bile. We studied ATP7B-deficient cells and animals to identify strategies to decrease copper toxicity in patients with WD. METHODS We used RNA-seq to compare gene expression patterns between wild-type and ATP7B-knockout HepG2 cells exposed to copper. We collected blood and liver tissues from Atp7b-/- and Atp7b+/- (control) rats (LPP) and mice; some mice were given 5 daily injections of an autophagy inhibitor (spautin-1) or vehicle. We obtained liver biopsies from 2 patients with WD in Italy and liver tissues from patients without WD (control). Liver tissues were analyzed by immunohistochemistry, immunofluorescence, cell viability, apoptosis assays, and electron and confocal microscopy. Proteins were knocked down in cell lines using small interfering RNAs. Levels of copper were measured in cell lysates, blood samples, liver homogenates, and subcellular fractions by spectroscopy. RESULTS After exposure to copper, ATP7B-knockout cells had significant increases in the expression of 103 genes that regulate autophagy (including MAP1LC3A, known as LC3) compared with wild-type cells. Electron and confocal microscopy visualized more autophagic structures in the cytoplasm of ATP7B-knockout cells than wild-type cells after copper exposure. Hepatocytes in liver tissues from patients with WD and from Atp7b-/- mice and rats (but not controls) had multiple autophagosomes. In ATP7B-knockout cells, mammalian target of rapamycin (mTOR) had decreased activity and was dissociated from lysosomes; this resulted in translocation of the mTOR substrate transcription factor EB to the nucleus and activation of autophagy-related genes. In wild-type HepG2 cells (but not ATP7B-knockout cells), exposure to copper and amino acids induced recruitment of mTOR to lysosomes. Pharmacologic inhibitors of autophagy or knockdown of autophagy proteins ATG7 and ATG13 induced and accelerated the death of ATP7B-knockout HepG2 cells compared with wild-type cells. Autophagy protected ATP7B-knockout cells from copper-induced death. CONCLUSION ATP7B-deficient hepatocytes, such as in those in patients with WD, activate autophagy in response to copper overload to prevent copper-induced apoptosis. Agents designed to activate this autophagic pathway might decrease copper toxicity in patients with WD.
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Affiliation(s)
- Elena V Polishchuk
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy; ITMO University, St. Petersburg, Russia; Institute of Biosciences and Bioresources CNR, Italy
| | - Assunta Merolla
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy
| | - Josef Lichtmannegger
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Alessia Romano
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy
| | - Alessia Indrieri
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy; Department of Translational Medical Science, "Federico II" University of Naples, Naples, Italy
| | - Ekaterina Y Ilyechova
- ITMO University, St. Petersburg, Russia; Department of Molecular Genetics, Institute of Experimental Medicine, St. Petersburg, Russia
| | - Mafalda Concilli
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy
| | - Rossella De Cegli
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy
| | - Roberta Crispino
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy
| | - Marta Mariniello
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy
| | | | - Giusy Ranucci
- Division of Metabolism, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Raffaele Iorio
- Department of Translational Medical Science, "Federico II" University of Naples, Naples, Italy
| | - Federico Pietrocola
- Equipe 11 labellisée Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Institut National de la Santé et de la Recherche Médicale, UMR1138, Equipe labellisée Ligue Nationale Contre le Cancer, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie, Paris, France; Cell Biology and Metabolomics Platforms, Gustave Roussy Cancer Campus, Villejuif, France
| | - Claudia Einer
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Sabine Borchard
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Andree Zibert
- Klinik für Transplantationsmedizin, Universitätsklinikum Münster, Münster, Germany
| | - Hartmut H Schmidt
- Klinik für Transplantationsmedizin, Universitätsklinikum Münster, Münster, Germany
| | | | | | - Brunella Franco
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy; Department of Translational Medical Science, "Federico II" University of Naples, Naples, Italy
| | - Guido Kroemer
- Equipe 11 labellisée Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Institut National de la Santé et de la Recherche Médicale, UMR1138, Equipe labellisée Ligue Nationale Contre le Cancer, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie, Paris, France; Cell Biology and Metabolomics Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden
| | - Hans Zischka
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Toxicology and Environmental Hygiene, Technical University Munich, Munich, Germany
| | - Roman S Polishchuk
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
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12
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Gerosa C, Fanni D, Congiu T, Piras M, Cau F, Moi M, Faa G. Liver pathology in Wilson's disease: From copper overload to cirrhosis. J Inorg Biochem 2019; 193:106-111. [PMID: 30703747 DOI: 10.1016/j.jinorgbio.2019.01.008] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 01/11/2019] [Accepted: 01/12/2019] [Indexed: 02/07/2023]
Abstract
Wilson's disease (WD) is a genetic metabolic disease strictly associated with liver cirrhosis. In this review, the genetic bases of the disease are discussed, with emphasis on the role of ATP7B (the Wilson disease protein) dysfunction as a determinant factor of systemic copper overload. Regarding the different multiple mutations described in WD patients, the peculiarity of Sardinian population is highlighted, Sardinians carrying a rare deletion in the promoter (5' UTR) of the WD gene. The role of epigenetic changes in the clinical presentation and evolution of liver disease in WD patients is also discussed, nutrition probably representing a relevantly risk factor in WD patients. The role of transmission electron microscopy in the diagnosis of WD-related liver disease is underlined. Mitochondrial changes, increased peroxisomes fat droplets, lipolysosomes and intranuclear glycogen inclusions are reported as the most frequent ultrastructural changes in the liver of WD carriers. The role of histochemical stains for copper is analyzed, and the Timm's method is suggested as the most sensitive one for revealing hepatic copper overload in all stage of WD. The marked variability of the histological liver changes occurring in WD is underlined simple steatosis may represent the only pathological changes, frequently associated with glycogenated nuclei. Mallory-Denk bodies lipogranulomas alcoholic and non-alcoholic fatty liver disease ending with bridging fibrosis and cirrhosis. Finally, the reversal of fibrosis as a possible therapeutic objective in WD is discussed.
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Affiliation(s)
- C Gerosa
- Division of Pathological, University of Cagliari AOU Cagliari, Cagliari, Italy
| | - D Fanni
- Division of Pathological, University of Cagliari AOU Cagliari, Cagliari, Italy
| | - T Congiu
- Division of Pathological, University of Cagliari AOU Cagliari, Cagliari, Italy
| | - M Piras
- Division of Pathological, University of Cagliari AOU Cagliari, Cagliari, Italy.
| | - F Cau
- Division of Pathological, San Gavino Hospital, ATS, San Gavino, Italy
| | - M Moi
- Division of Pathological, University of Cagliari AOU Cagliari, Cagliari, Italy
| | - G Faa
- Division of Pathological, University of Cagliari AOU Cagliari, Cagliari, Italy
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13
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Kardos J, Héja L, Simon Á, Jablonkai I, Kovács R, Jemnitz K. Copper signalling: causes and consequences. Cell Commun Signal 2018; 16:71. [PMID: 30348177 PMCID: PMC6198518 DOI: 10.1186/s12964-018-0277-3] [Citation(s) in RCA: 127] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 09/24/2018] [Indexed: 12/18/2022] Open
Abstract
Copper-containing enzymes perform fundamental functions by activating dioxygen (O2) and therefore allowing chemical energy-transfer for aerobic metabolism. The copper-dependence of O2 transport, metabolism and production of signalling molecules are supported by molecular systems that regulate and preserve tightly-bound static and weakly-bound dynamic cellular copper pools. Disruption of the reducing intracellular environment, characterized by glutathione shortage and ambient Cu(II) abundance drives oxidative stress and interferes with the bidirectional, copper-dependent communication between neurons and astrocytes, eventually leading to various brain disease forms. A deeper understanding of of the regulatory effects of copper on neuro-glia coupling via polyamine metabolism may reveal novel copper signalling functions and new directions for therapeutic intervention in brain disorders associated with aberrant copper metabolism.
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Affiliation(s)
- Julianna Kardos
- Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, Budapest, 1117 Hungary
| | - László Héja
- Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, Budapest, 1117 Hungary
| | - Ágnes Simon
- Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, Budapest, 1117 Hungary
| | - István Jablonkai
- Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, Budapest, 1117 Hungary
| | - Richard Kovács
- Institute of Neurophysiology, Charité-Universitätsmedizin, Berlin, Germany
| | - Katalin Jemnitz
- Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, Budapest, 1117 Hungary
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14
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Velie BD, Fegraeus KJ, Solé M, Rosengren MK, Røed KH, Ihler CF, Strand E, Lindgren G. A genome-wide association study for harness racing success in the Norwegian-Swedish coldblooded trotter reveals genes for learning and energy metabolism. BMC Genet 2018; 19:80. [PMID: 30157760 PMCID: PMC6114527 DOI: 10.1186/s12863-018-0670-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Accepted: 08/20/2018] [Indexed: 12/19/2022] Open
Abstract
Background Although harness racing is of high economic importance to the global equine industry, significant genomic resources have yet to be applied to mapping harness racing success. To identify genomic regions associated with harness racing success, the current study performs genome-wide association analyses with three racing performance traits in the Norwegian-Swedish Coldblooded Trotter using the 670 K Axiom Equine Genotyping Array. Results Following quality control, 613 horses and 359,635 SNPs were retained for further analysis. After strict Bonferroni correction, nine genome-wide significant SNPs were identified for career earnings. No genome-wide significant SNPs were identified for number of gallops or best km time. However, four suggestive genome-wide significant SNPs were identified for number of gallops, while 19 were identified for best km time. Multiple genes related to intelligence, energy metabolism, and immune function were identified as potential candidate genes for harness racing success. Conclusions Apart from the physiological requirements needed for a harness racing horse to be successful, the results of the current study also advocate learning ability and memory as important elements for harness racing success. Further exploration into the mental capacity required for a horse to achieve racing success is likely warranted. Electronic supplementary material The online version of this article (10.1186/s12863-018-0670-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Brandon D Velie
- Department of Animal Breeding & Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
| | - Kim Jäderkvist Fegraeus
- Department of Animal Breeding & Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Marina Solé
- Department of Animal Breeding & Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Maria K Rosengren
- Department of Animal Breeding & Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Knut H Røed
- Department of Basic Sciences and Aquatic Medicine, Norwegian University of Life Sciences, Oslo, Norway
| | - Carl-Fredrik Ihler
- Department of Companion Animal Clinical Sciences, Norwegian School of Veterinary Science, Oslo, Norway
| | - Eric Strand
- Department of Companion Animal Clinical Sciences, Norwegian School of Veterinary Science, Oslo, Norway
| | - Gabriella Lindgren
- Department of Animal Breeding & Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.,Department of Biosystems, KU Leuven, 3001, Leuven, Belgium
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15
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Benham AM. Endoplasmic Reticulum redox pathways: in sickness and in health. FEBS J 2018; 286:311-321. [PMID: 30062765 DOI: 10.1111/febs.14618] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 06/25/2018] [Accepted: 07/27/2018] [Indexed: 02/06/2023]
Abstract
The Endoplasmic Reticulum (ER) is the major site for secretory protein production in eukaryotic cells and like an efficient factory, it has the capacity to expand or contract its output depending on the demand for its services. A primary function of the ER is to co-ordinate the quality control of proteins as they enter this folding factory at the base of the secretory pathway. Reduction-oxidation (redox) reactions have an important role to play in the quality control process, through the provision of disulphide bonds and by maintaining a favourable redox environment for oxidative protein folding. The ER is also a major contributor to calcium homeostasis and is a key site for lipid biosynthesis, two processes that additionally impact upon, and are influenced by, redox in the ER compartment.
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16
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Ariöz C, Li Y, Wittung-Stafshede P. The six metal binding domains in human copper transporter, ATP7B: molecular biophysics and disease-causing mutations. Biometals 2017; 30:823-840. [PMID: 29063292 PMCID: PMC5684295 DOI: 10.1007/s10534-017-0058-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 10/05/2017] [Indexed: 12/16/2022]
Abstract
Wilson Disease (WD) is a hereditary genetic disorder, which coincides with a dysfunctional copper (Cu) metabolism caused by mutations in ATP7B, a membrane-bound P1B-type ATPase responsible for Cu export from hepatic cells. The N-terminal part (~ 600 residues) of the multi-domain 1400-residue ATP7B constitutes six metal binding domains (MBDs), each of which can bind a copper ion, interact with other ATP7B domains as well as with different proteins. Although the ATP7B's MBDs have been investigated in vitro and in vivo intensively, it remains unclear how these domains modulate overall structure, dynamics, stability and function of ATP7B. The presence of six MBDs is unique to mammalian ATP7B homologs, and many WD causing missense mutations are found in these domains. Here, we have summarized previously reported in vitro biophysical data on the MBDs of ATP7B and WD point mutations located in these domains. Besides the demonstration of where the research field stands today, this review showcasts the need for further biophysical investigation about the roles of MBDs in ATP7B function. Molecular mechanisms of ATP7B are important not only in the development of new WD treatment but also for other aspects of human physiology where Cu transport plays a role.
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Affiliation(s)
- Candan Ariöz
- Department of Biology and Biological Engineering, Division of Chemical Biology, Chalmers University of Technology, Kemigården 4, 412 96 Gothenburg, Sweden
| | - Yaozong Li
- Department of Chemistry, Umeå University, Kemihuset A, Linnaeus väg 10, 901 87 Umeå, Sweden
| | - Pernilla Wittung-Stafshede
- Department of Biology and Biological Engineering, Division of Chemical Biology, Chalmers University of Technology, Kemigården 4, 412 96 Gothenburg, Sweden
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17
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Ranucci G, Polishchuck R, Iorio R. Wilson's disease: Prospective developments towards new therapies. World J Gastroenterol 2017; 23:5451-5456. [PMID: 28852304 PMCID: PMC5558108 DOI: 10.3748/wjg.v23.i30.5451] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 04/11/2017] [Accepted: 07/22/2017] [Indexed: 02/06/2023] Open
Abstract
Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism, caused by mutations in the ATP7B gene. A clear demand for novel WD treatment strategies has emerged. Although therapies using zinc salts and copper chelators can effectively cure WD, these drugs exhibit limitations in a substantial pool of WD patients who develop intolerance and/or severe side effects. Several lines of research have indicated intriguing potential for novel strategies and targets for development of new therapies. Here, we review these new approaches, which comprise correction of ATP7B mutants and discovery of new compounds that circumvent ATP7B-deficiency, as well as cell and gene therapies. We also discuss whether and when these new therapeutic strategies will be translated into clinical use, according to the key requirements for clinical trials that remain to be met. Finally, we discuss the hope for the current rapidly developing research on molecular mechanisms underlying WD pathogenesis and for the related potential therapeutic targets to provide a solid foundation for the next generation of WD therapies that may lead to an effective, tolerable and safe cure.
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18
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Hegde RN, Subramanian A, Pothukuchi P, Parashuraman S, Luini A. Rare ER protein misfolding-mistrafficking disorders: Therapeutic developments. Tissue Cell 2017; 49:175-185. [PMID: 28222887 DOI: 10.1016/j.tice.2017.02.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 02/02/2017] [Accepted: 02/04/2017] [Indexed: 12/16/2022]
Abstract
The presence of a functional protein at the appropriate location in the cell is the result of the processes of transcription, translation, folding and trafficking to the correct destination. There are numerous diseases that are caused by protein misfolding, mainly due to mutations in the respective gene. The consequences of this misfolding may be that proteins effectively lose their function, either by being removed by the cellular quality control machinery or by accumulating at the incorrect intracellular or extracellular location. A number of mutations that lead to protein misfolding and affect trafficking to the final destination, e.g. Cystic fibrosis, Wilson's disease, and Progressive Familial Intrahepatic 1 cholestasis, result in proteins that retain partial function if their folding and trafficking is restored either by molecular or pharmacological means. In this review, we discuss several mutant proteins within this class of misfolding diseases and provide an update on the status of molecular and therapeutic developments and potential therapeutic strategies being developed to counter these diseases.
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Affiliation(s)
| | - Advait Subramanian
- Institute of Protein Biochemistry, National Research Council, Naples, Italy
| | | | | | - Alberto Luini
- Institute of Protein Biochemistry, National Research Council, Naples, Italy; Istituto di Ricovero e Cura a Carattere Scientifico SDN, Naples, Italy
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