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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\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    strain with a substitution of a conserved histidine (H828Q) in the ATP7B ortholog\n                    <jats:italic>cua\u20101<\/jats:italic>\n                    corresponding to the most common ATP7B variant (H1069Q) that causes WD.\n                    <jats:italic>cua\u20101<\/jats:italic>\n                    mutant animals exhibited very poor resistance to Cu compared to the wild\u2010type 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\n                    <jats:italic>cua\u20101<\/jats:italic>\n                    mutant animals exposed to Cu. Further investigation suggested that mutant CUA\u20101 is retained and degraded in the endoplasmic reticulum, similarly to human ATP7B\u2010H1069Q. As a consequence, the mutant protein does not allow animals to counteract Cu toxicity. Notably, pharmacological correctors of ATP7B\u2010H1069Q reduced Cu toxicity in\n                    <jats:italic>cua\u20101<\/jats:italic>\n                    mutants indicating that similar pathogenic molecular pathways might be activated by the H\/Q substitution and, therefore, targeted for rescue of ATP7B\/CUA\u20101 function. Taken together, our findings suggest that the newly generated\n                    <jats:italic>cua\u20101<\/jats:italic>\n                    mutant strain represents an excellent model for Cu toxicity studies in WD.\n                  <\/jats:p>","DOI":"10.1111\/tra.12920","type":"journal-article","created":{"date-parts":[[2023,10,27]],"date-time":"2023-10-27T05:51:28Z","timestamp":1698385888000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A new\n                    <i>Caenorhabditis elegans<\/i>\n                    model to study copper toxicity in Wilson disease"],"prefix":"10.1111","volume":"25","author":[{"given":"Federico","family":"Catalano","sequence":"first","affiliation":[{"name":"Cell Biology and Disease Mechanisms Program Telethon Institute of Genetics and Medicine (TIGEM)  Pozzuoli Italy"},{"name":"Institute of Biosciences and BioResources National Research Council (CNR)  Napoli 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