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
-
- Animals
- Brain/metabolism
- Brain/pathology
- Cerebellum/metabolism*
- Cerebellum/pathology
- Disease Models, Animal
- Down Syndrome/genetics*
- Down Syndrome/pathology
- Humans
- Neurons/metabolism*
- Neurons/pathology
- Phosphorylation/genetics
- Protein Kinases/genetics*
- Protein Serine-Threonine Kinases/genetics*
- Protein-Tyrosine Kinases/genetics*
- Purkinje Cells/metabolism
- Purkinje Cells/pathology
- Zebrafish/genetics
- Zebrafish Proteins/genetics*
- PubMed
- 34090874 Full text @ J. Biol. Chem.
Citation
Buchberger, A., Schepergerdes, L., Flaßhoff, M., Kunick, C., Köster, R.W. (2021) A novel inhibitor rescues cerebellar defects in a zebrafish model of Down Syndrome-associated kinase Dyrk1A overexpression. The Journal of biological chemistry. 297(1):100853.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping