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

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

Authors :
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 E. X.
Puchkova, Ludmila V.
Di Schiavi, Elia
Source :
Traffic; Jan2024, Vol. 25 Issue 1, p1-20, 20p
Publication Year :
2024

Abstract

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
13989219
Volume :
25
Issue :
1
Database :
Complementary Index
Journal :
Traffic
Publication Type :
Academic Journal
Accession number :
175056118
Full Text :
https://doi.org/10.1111/tra.12920