Upregulation of three Drosophila homologs of human chromosome 21 genes alters synaptic function: Implications for Down syndrome
Upregulation of three Drosophila homologs of human chromosome 21 genes alters synaptic function: Implications for Down syndrome
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DOI：
10.1073/pnas.0904397106
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发表时间：
2009-10-06
影响因子：
11.1
通讯作者：
Min, Kyung-Tai
中科院分区：
文献类型：
--
作者：
Chang, Karen T.;Min, Kyung-Tai
在唐氏综合征（DS）脑的神经元水平，有证据表明，改变形状，数量和密度的突触，以及异常的内吞作用与积累的扩大内涵体，这表明参与突触囊泡回收的蛋白质可能在DS神经元中发挥关键作用。然而，这些异常现象背后的确切机制尚不清楚。我们推测，位于人类21号染色体上的dap 160/itsn 1，synj/synj 1和nla/dap 11 3个基因的过表达在DS神经元中起重要作用。在这里，我们系统地研究了多基因过表达对突触形态和内吞作用的影响，以确定可能的显性基因或基因。我们发现，个别基因的过度表达导致异常的突触形态，但所有三个基因是必要的，导致受损的囊泡回收和影响运动活力。此外，我们报告dap 160过表达改变了synaptojanin的亚细胞分布，nla过表达调节synaptojanin的磷酸肌醇5'磷酸酶活性。这些发现意味着恢复这些基因中的任何一个的水平可以减少DS中所见的内吞缺陷。
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.