PUBLICATION

A novel inhibitor rescues cerebellar defects in a zebrafish model of Down Syndrome-associated kinase Dyrk1A overexpression

Authors
Buchberger, A., Schepergerdes, L., Flaßhoff, M., Kunick, C., Köster, R.W.
ID
ZDB-PUB-210608-3
Date
2021
Source
The Journal of biological chemistry   297(1): 100853 (Journal)
Registered Authors
Köster, Reinhard W.
Keywords
Down Syndrome, Dyrk1A, Purkinje cell, cerebellum, imaging, neurological disease, zebrafish
MeSH Terms
  • Protein Kinases/genetics*
  • Zebrafish Proteins/genetics*
  • Zebrafish/genetics
  • Neurons/metabolism*
  • Neurons/pathology
  • Purkinje Cells/metabolism
  • Purkinje Cells/pathology
  • Disease Models, Animal
  • Protein Serine-Threonine Kinases/genetics*
  • Brain/metabolism
  • Brain/pathology
  • Down Syndrome/genetics*
  • Down Syndrome/pathology
  • Phosphorylation/genetics
  • Animals
  • Protein-Tyrosine Kinases/genetics*
  • Humans
  • Cerebellum/metabolism*
  • Cerebellum/pathology
(all 19)
PubMed
34090874 Full text @ J. Biol. Chem.
Abstract
The highly conserved dual specificity tyrosine phosphorylation regulated kinase 1A (Dyrk1A) plays crucial roles during central nervous system development and homeostasis. Furthermore, its hyperactivity is considered responsible for some neurological defects in individuals with Down Syndrome (DS). We set out to establish a zebrafish model expressing human Dyrk1A that could be further used to characterize the interaction between Dyrk1A and neurological phenotypes. First, we revealed the prominent expression of dyrk1a homologs in cerebellar neurons in the zebrafish larval and adult brain. Overexpression of human dyrk1a in postmitotic cerebellar Purkinje neurons resulted in a structural misorganization of the Purkinje cells in cerebellar hemispheres and a compaction of this cell population. This impaired Purkinje cell organization was progressive, leading to an age-dependent dispersal of Purkinje neurons throughout the cerebellar molecular layer with larval swim deficits resulting in miscoordination of swimming and reduced exploratory behavior in aged adults. We also found that the structural misorganization of the larval Purkinje cell layer could be rescued by pharmacological treatment with Dyrk1A inhibitors. We further reveal the in vivo efficiency of a novel selective Dyrk1A inhibitor, KuFal194. These findings demonstrate that the zebrafish is a well-suited vertebrate organism to genetically model severe neurological diseases with single cell type-specificity. Such models can be used to relate molecular malfunction to cellular deficits, impaired tissue formation, and organismal behavior, and can also be used for pharmacological compound testing and validation.
Genes / Markers
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Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
b2
    Unknown
    bz4TgTransgenic Insertion
      bz19TgTransgenic Insertion
        1 - 3 of 3
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        Human Disease / Model
        Human Disease Fish Conditions Evidence
        Down syndromebz19Tgstandard conditionsTAS
        1 - 1 of 1
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        Sequence Targeting Reagents
        No data available
        Fish
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        Antibodies
        Orthology
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        Engineered Foreign Genes
        Marker Marker Type Name
        mCloverEFGmClover
        TagRFPEFGTagRFP
        1 - 2 of 2
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