A new Caenorhabditis elegans model to study copper toxicity in Wilson disease.

Autor: Catalano F; Cell Biology and Disease Mechanisms Program, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.; Institute of Biosciences and BioResources, National Research Council (CNR), Napoli, Italy., O'Brien TJ; Behavioural Phenomics Research Group, MRC London Institute of Medical Sciences, London, UK.; Institute of Clinical Sciences, Imperial College London, London, UK., Mekhova AA; Research Center of Advanced Functional Materials and Laser Communication Systems, ADTS Institute, ITMO University, St. Petersburg, Russia., Sepe LV; Cell Biology and Disease Mechanisms Program, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy., Elia M; Cell Biology and Disease Mechanisms Program, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy., De Cegli R; Cell Biology and Disease Mechanisms Program, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy., Gallotta I; Cell Biology and Disease Mechanisms Program, 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., Santonicola P; Institute of Biosciences and BioResources, National Research Council (CNR), Napoli, Italy., Zampi G; Institute of Biosciences and BioResources, National Research Council (CNR), Napoli, Italy., Ilyechova EY; 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., Romanov AA; Department of Applied Mathematics, Institute of Applied Mathematics and Mechanics, Peter the Great Polytechnic University, St. Petersburg, Russia., Samuseva PD; Research Center of Advanced Functional Materials and Laser Communication Systems, ADTS Institute, ITMO University, St. Petersburg, Russia., Salzano J; Cell Biology and Disease Mechanisms Program, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy., Petruzzelli R; Cell Biology and Disease Mechanisms Program, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.; Scuola Superiore Meridionale, School of Advanced Studies, Genomics and Experimental Medicine Program, University of Naples Federico II, Naples, Italy., Polishchuk EV; Cell Biology and Disease Mechanisms Program, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.; Institute of Biosciences and BioResources, National Research Council (CNR), Napoli, Italy., Indrieri A; Cell Biology and Disease Mechanisms Program, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.; Institute for Genetic and Biomedical Research, National Research Council (CNR), Milan, Italy., Kim BE; Department of Animal and Avian Sciences, University of Maryland, College Park, Maryland, USA., Brown AEX; Behavioural Phenomics Research Group, MRC London Institute of Medical Sciences, London, UK.; Institute of Clinical Sciences, Imperial College London, London, UK., Puchkova LV; Research Center of Advanced Functional Materials and Laser Communication Systems, ADTS Institute, ITMO University, St. Petersburg, Russia., Di Schiavi E; Institute of Biosciences and BioResources, National Research Council (CNR), Napoli, Italy.; Institute of Genetics and Biophysics Adriano Buzzati-Traverso (IGB-ABT), National Research Council (CNR), Napoli, Italy., Polishchuk RS; Cell Biology and Disease Mechanisms Program, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.; Institute for Genetic and Biomedical Research, National Research Council (CNR), Milan, Italy.
Jazyk: angličtina
Zdroj: Traffic (Copenhagen, Denmark) [Traffic] 2024 Jan; Vol. 25 (1), pp. e12920. Date of Electronic Publication: 2023 Oct 27.
DOI: 10.1111/tra.12920
Abstrakt: 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.
(© 2023 The Authors. Traffic published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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