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

Details

• Alternative Title:
  Traffic
• Personal Author:
  Catalano, Federico ; O’Brien, Thomas J ; Mekhova, Aleksandra A ; Sepe, Lucia Vittoria ; Elia, Mariantonietta ; De Cegli, Rossella ; Gallotta, Ivan ; Santonicola, Pamela ; Zampi, Giuseppina ; Ilyechova, Ekaterina Y ; Romanov, Aleksei A ; Samuseva, Polina D ; Salzano, Josephine ; Petruzzelli, Raffaella ; Polishchuk, Elena V. ; Indrieri, Alessia ; Kim, Byung-Eun ; Brown, André EX ; Puchkova, Ludmila V ; Di Schiavi, Elia ; Polishchuk, Roman S.
• Description:
  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.
• Subjects:
  Animals Caenorhabditis Elegans Copper Copper-Transporting ATPases Hepatocytes Hepatolenticular Degeneration Humans
• Keywords:
  Animal Model ATP7B C. Elegans Copper Homeostasis CUA-1 Endoplasmic Reticulum Lysosomes Wilson Disease
• Source:
  Traffic. 25(1):e12920
• Pubmed ID:
  37886910
• Pubmed Central ID:
  PMC10841361
• Document Type:
  Journal Article
• Funding:
  MC-A658-5TY30/MRC_/Medical Research CouncilUnited Kingdom/ ; P40 OD010440/CD/ODCDC CDC HHSUnited States/ ; P40 OD010440/OD/NIH HHSUnited States/ ; MC_UP_1102/6/MRC_/Medical Research CouncilUnited Kingdom/ ; R01 DK129599/DK/NIDDK NIH HHSUnited States/ ; R01 DK129599/NH/NIH HHSUnited States/
• Volume:
  25
• Issue:
  1
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:9f2f821db22e695171277bce283f45fc5289028c3753178594ecb91e33fbbcf6c53bf569ff1f409f2a96c9b30e1a3729fa47af337591c56b8b9ec01425bca2b2
• Download URL:
  https://stacks.cdc.gov/view/cdc/147707/cdc_147707_DS1.pdf
• File Type:
  [PDF - 2.34 MB ]