Overexpression of Dyrk1A causes the defects in synaptic vesicle endocytosis.
Trisomy 21-linked Dyrk1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A) overexpression is implicated in pathogenic mechanisms underlying mental retardation in Down syndrome (DS). It is known to phosphorylate multiple substrates including endocytic proteins in vitro, but the functional consequence of Dyrk1A-mediated phosphorylation on endocytosis has never been investigated. Here, we show that overexpression of Dyrk1A causes defects in clathrin-mediated endocytosis and specifically, in the recruitment of endocytic proteins to clathrin-coated pits in fibroblasts. Synaptic vesicle endocytosis also significantly slowed down as a result of Dyrk1A overexpression in cultured hippocampal neurons. These effects are dependent on Dyrk1A kinase activity. The inhibitory effect of Dyrk1A on synaptic vesicle endocytosis was confirmed in neuronal cultures derived from transgenic mice overexpressing Dyrk1A at levels found in DS. Pharmacological blockade of Dyrk1A with epigallocatechin gallate rescued the endocytic phenotypes found in transgenic neurons. Together, our results suggest that aberrant Dyrk1A-mediated phosphorylation of the endocytic machinery perturbs synaptic vesicle endocytosis, which may contribute to synaptic dysfunctions and cognitive deficits associated with DS.
Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.
Yoonju
Y
Kim
Joohyun
J
Park
Woo-Joo
WJ
Song
Sunghoe
S
Chang
D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004705:Endocytosis / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000235:genetics*; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics*; D051381:Rats; D013572:Synaptic Vesicles / Q000235:genetics* / Q000473:pathology* / Q000502:physiology; D000097603:Dyrk Kinases
D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases