PUBLICATION

Genetic model of UBA5 deficiency highlights the involvement of both peripheral and central nervous systems and identifies widespread mitochondrial abnormalities

Authors
Serrano, R.J., Oorschot, V., Palipana, D., Calcinotto, V., Sonntag, C., Ramm, G., Bryson-Richardson, R.J.
ID
ZDB-PUB-231204-11
Date
2023
Source
Brain communications   5: fcad317fcad317 (Journal)
Registered Authors
Bryson-Richardson, Robert, Calcinotto, Vanessa, Palipana, Dashika, Serrano, Rita, Sonntag, Carmen
Keywords
UBA5, encephalopathy, mitochondria, ufmylation, zebrafish
MeSH Terms
none
PubMed
38046095 Full text @ Brain Commun
Abstract
Variants in UBA5 have been reported to cause neurological disease with impaired motor function, developmental delay, intellectual disability and brain pathology as recurrent clinical manifestations. UBA5 encodes a ubiquitin-activating-like enzyme that activates ufmylation, a post-translational ubiquitin-like modification pathway, which has been implicated in neurodevelopment and neuronal survival. The reason behind the variation in severity and clinical manifestations in affected individuals and the signal transduction pathways regulated by ufmylation that compromise the nervous system remains unknown. Zebrafish have emerged as a powerful model to study neurodegenerative disease due to its amenability for in vivo analysis of muscle and neuronal tissues, high-throughput examination of motor function and rapid embryonic development allowing an examination of disease progression. Using clustered regularly interspaced short palindromic repeats-associated protein 9 genome editing, we developed and characterized zebrafish mutant models to investigate disease pathophysiology. uba5 mutant zebrafish showed a significantly impaired motor function accompanied by delayed growth and reduced lifespan, reproducing key phenotypes observed in affected individuals. Our study demonstrates the suitability of zebrafish to study the pathophysiology of UBA5-related disease and as a powerful tool to identify pathways that could reduce disease progression. Furthermore, uba5 mutants exhibited widespread mitochondrial damage in both the nervous system and the skeletal muscle, suggesting that a perturbation of mitochondrial function may contribute to disease pathology.
Genes / Markers
Figures
Figure Gallery (6 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
knu3TgTransgenic Insertion
    mnu11
      Insertion
      mnu12
        Small Deletion
        1 - 3 of 3
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        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        Target Reagent Reagent Type
        uba5CRISPR1-uba5CRISPR
        uba5CRISPR2-uba5CRISPR
        1 - 2 of 2
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        Fish
        Antibodies
        Name Type Antigen Genes Isotypes Host Organism
        Ab1-ncampolyclonal
          Rabbit
          Ab1-tubamonoclonal
            IgG2bMouse
            Ab1-uba5polyclonal
              IgGRabbit
              Ab1-ufm1polyclonal
                IgGRabbit
                Ab2-pink1monoclonal
                  IgGRabbit
                  Ab2-ufm1monoclonal
                    IgGRabbit
                    1 - 6 of 6
                    Show
                    Orthology
                    No data available
                    Engineered Foreign Genes
                    Marker Marker Type Name
                    EGFPEFGEGFP
                    1 - 1 of 1
                    Show
                    Mapping
                    No data available