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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.)

Background: There is little consensus on factors associated with survival in foals with septic arthritis and limited data on long-term racing performance of Thoroughbred foals treated for septic arthritis. A more thorough understanding of short- and long-term outcome is necessary to help inform owners, and subsequently guide treatment., Objectives: To investigate factors associated with survival, and to analyse racing performance of foals with septic arthritis compared with their maternal siblings., Study Design: Retrospective cohort and a case-control study., Methods: Veterinary clinical records of Thoroughbred foals ≤180 days old that underwent arthroscopic, cannulae or through-and-through needle lavage for the treatment of septic arthritis between 2009 and 2015 were reviewed. Data included signalment, and clinicopathological information. The dam's foaling records were reviewed and the lifetime racing records were obtained for affected foals and two of their maternal siblings. Logistic regression analysis was used to determine factors associated with survival to discharge or racing. Comparisons between treated foals and their maternal siblings were made., Results: Ninety (78%) of 115 foals diagnosed with septic arthritis were discharged alive. Foals <26 days old at the time of admission were five times less likely (P = .003) and foals with concurrent multisystemic disease were six times less likely (P = .02) to be discharged alive. Sixty (67%) foals discharged alive started in ≥1 race, and there was no difference in the proportion of foals that started in a race or racing performance between foals treated for septic arthritis and their maternal siblings., Main Limitations: Retrospective study design, limited number of foals with multiple joint involvement and failure to accurately record duration of clinical signs., Conclusions: Foals treated for septic arthritis at the Scone Equine Hospital, New South Wales, Australia had a good prognosis for survival, and for this cohort, foals that survived to discharge had a similar ability to race as their maternal siblings., (© 2020 EVJ Ltd.)