A new Caenorhabditis elegans model to study copper toxicity in Wilson disease.
Federico Catalano, Thomas J O'Brien, Aleksandra A Mekhova, Lucia Vittoria Sepe, Mariantonietta Elia, Rossella De Cegli, Ivan Gallotta, Pamela Santonicola, Giuseppina Zampi, Ekaterina Y Ilyechova, Aleksei A Romanov, Polina D Samuseva, Josephine Salzano, Raffaella Petruzzelli, Elena V Polishchuk, Alessia Indrieri, Byung-Eun Kim, André E X Brown, Ludmila V Puchkova, Elia Di Schiavi, Roman S Polishchuk
Author Information
Federico Catalano: Cell Biology and Disease Mechanisms Program, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
Thomas J O'Brien: Behavioural Phenomics Research Group, MRC London Institute of Medical Sciences, London, UK. ORCID
Aleksandra A Mekhova: Research Center of Advanced Functional Materials and Laser Communication Systems, ADTS Institute, ITMO University, St. Petersburg, Russia.
Lucia Vittoria Sepe: Cell Biology and Disease Mechanisms Program, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
Mariantonietta Elia: Cell Biology and Disease Mechanisms Program, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy. ORCID
Rossella De Cegli: Cell Biology and Disease Mechanisms Program, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
Ivan Gallotta: Cell Biology and Disease Mechanisms Program, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
Pamela Santonicola: Institute of Biosciences and BioResources, National Research Council (CNR), Napoli, Italy.
Giuseppina Zampi: Institute of Biosciences and BioResources, 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.
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: Cell Biology and Disease Mechanisms Program, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
Raffaella Petruzzelli: Cell Biology and Disease Mechanisms Program, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy. ORCID
Elena V Polishchuk: Cell Biology and Disease Mechanisms Program, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
Alessia Indrieri: Cell Biology and Disease Mechanisms Program, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
Byung-Eun Kim: Department of Animal and Avian Sciences, University of Maryland, College Park, Maryland, USA.
André E X Brown: Behavioural Phenomics Research Group, MRC London Institute of Medical Sciences, London, UK.
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, National Research Council (CNR), Napoli, Italy.
Roman S Polishchuk: Cell Biology and Disease Mechanisms Program, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
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.
