Upregulation of three Drosophila homologs of human chromosome 21 genes alters synaptic function: implications for Down syndrome.
At the neuronal level of Down syndrome (DS) brains, there are evidences of altered shape, number, and density of synapses, as well as aberrant endocytosis associated with accumulation of enlarged endosomes, suggesting that proteins involved in synaptic vesicle recycling may play key roles in DS neurons. However, the exact mechanism underlying those anomalies is not well understood. We hypothesize that overexpression of three genes, dap160/itsn1, synj/synj1, and nla/dscr1, located on human chromosome 21 play important roles in DS neurons. Here, we systematically investigate the effects of multiple gene overexpression on synaptic morphology and endocytosis to identify possible dominant gene or genes. We found that overexpression of individual genes lead to abnormal synaptic morphology, but all three genes are necessary to cause impaired vesicle recycling and affect locomotor vigor. Furthermore, we report that dap160 overexpression alters the subcellular distribution of synaptojanin, and overexpression of nla regulates the phosphoinositol 5' phosphatase activity of synaptojanin. These findings imply that restoring the level of any one of these genes may reduce endocytic defects seen in DS.
Chang
Karen T
KT
Department of Biology, Indiana University, Bloomington, IN 47405, USA.
Min
Kyung-Tai
KT
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D002135:Calcium-Binding Proteins; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D004268:DNA-Binding Proteins; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D004705:Endocytosis; D005071:Evoked Potentials; D019706:Excitatory Postsynaptic Potentials; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007814:Larva / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008954:Models, Biological; D009043:Motor Activity / Q000502:physiology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000502:physiology; D015854:Up-Regulation; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000099182:Phosphoinositide 5-Phosphatases
D033942:Adaptor Proteins, Vesicular Transport; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D010744:Phosphoric Monoester Hydrolases; D033921:Vesicular Transport Proteins; D000099182:Phosphoinositide 5-Phosphatases; C113692:Dap160 protein, Drosophila; C485568:ITSN1 protein, human; C108612:RCAN1 protein, human; C513393:Sra protein, Drosophila; C097702:synaptojanin