Division of Cellular and Molecular Neurobiology, Zoological Institute, Technische Universität Braunschweig, Braunschweig, Germany.
Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Braunschweig, Germany.
J Biol Chem. 2021 Jul;297(1):100853. doi: 10.1016/j.jbc.2021.100853. Epub 2021 Jun 4.
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. 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 brains. 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.
高度保守的双特异性酪氨酸磷酸化调节激酶 1A（Dyrk1A）在中枢神经系统发育和稳态中发挥着关键作用。此外，其过度活跃被认为是唐氏综合征患者一些神经缺陷的原因。我们着手建立一种表达人 Dyrk1A 的斑马鱼模型，该模型可进一步用于研究 Dyrk1A 与神经表型之间的相互作用。首先，我们揭示了斑马鱼幼虫和成年大脑中小脑神经元中 dyrk1a 同源物的显著表达。在有丝分裂后小脑浦肯野神经元中过表达人 Dyrk1A 导致小脑半球浦肯野细胞的结构组织紊乱和该细胞群体的密集。这种受损的浦肯野细胞组织紊乱是进行性的，导致浦肯野神经元随年龄依赖性地在整个小脑分子层中扩散，导致幼虫游泳能力下降，成年后探索行为减少。我们还发现，用 Dyrk1A 抑制剂进行药理学治疗可以挽救幼虫浦肯野细胞层的结构组织紊乱。我们进一步揭示了一种新型选择性 Dyrk1A 抑制剂 KuFal194 的体内效率。这些发现表明，斑马鱼是一种非常适合的脊椎动物模型，可用于对具有单细胞特异性的严重神经疾病进行基因建模。这种模型可用于将分子功能障碍与细胞缺陷、组织形成受损和机体行为相关联，还可用于药物化合物的测试和验证。
