Altered spinogenesis in iPSC-derived cortical neurons from patients with autism carrying de novo SHANK3 mutations
Altered spinogenesis in iPSC-derived cortical neurons from patients with autism carrying de novo SHANK3 mutations
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DOI：
10.1038/s41598-018-36993-x
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发表时间：
2019-01-14
影响因子：
4.6
通讯作者：
Cloez-Tayarani, Isabelle
中科院分区：
文献类型：
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作者：
Gouder, Laura;Vitrac, Aline;Cloez-Tayarani, Isabelle
突触蛋白SHANK3编码一种多结构域支架蛋白，在神经元兴奋性突触的突触后密度处表达。我们以前在自闭症谱系障碍(ASD)患者中发现了新的SHANK3突变，并表明SHANK3代表ASD的主要基因之一。在这里，我们分析了来自四名携带SHANK3新截断突变的ASD患者的诱导多能干细胞来源的锥体皮质神经元。在神经干细胞分化后40~45d，锥体神经元的树突棘呈现出不同的形态：丝状足突、细刺、短棘和肌肉刺，用GFP标记和免疫荧光进行三维测量。与三个对照组相比，我们观察到SHANK3mRNA水平显著降低(不到对照组的50%)，与树突棘密度以及整个脊柱和脊柱头部体积显著减少相关。这些通过分析患者基因组背景中的从头SHANK3突变而获得的结果，为ASD患者中存在突触异常提供了进一步的支持。
The synaptic protein SHANK3 encodes a multidomain scaffold protein expressed at the postsynaptic density of neuronal excitatory synapses. We previously identified de novo SHANK3 mutations in patients with autism spectrum disorders (ASD) and showed that SHANK3 represents one of the major genes for ASD. Here, we analyzed the pyramidal cortical neurons derived from induced pluripotent stem cells from four patients with ASD carrying SHANK3 de novo truncating mutations. At 40-45 days after the differentiation of neural stem cells, dendritic spines from pyramidal neurons presented variable morphologies: filopodia, thin, stubby and muschroom, as measured in 3D using GFP labeling and immunofluorescence. As compared to three controls, we observed a significant decrease in SHANK3 mRNA levels (less than 50% of controls) in correlation with a significant reduction in dendritic spine densities and whole spine and spine head volumes. These results, obtained through the analysis of de novo SHANK3 mutations in the patients' genomic background, provide further support for the presence of synaptic abnormalities in a subset of patients with ASD.