Critical roles of αII spectrin in brain development and epileptic encephalopathy
Critical roles of αII spectrin in brain development and epileptic encephalopathy
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DOI：
10.1172/jci95743
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发表时间：
2018-02-01
影响因子：
15.9
通讯作者：
Parent, Jack M.
中科院分区：
文献类型：
--
作者：
Wang, Yu;Ji, Tuo;Parent, Jack M.
非红细胞α-血影蛋白-1(SPTAN1)基因编码细胞骨架蛋白α-II血影蛋白。SPTAN1基因突变导致早期婴儿癫痫脑病5型(EIEE5)；然而，αII血影蛋白在神经发育和EIEE5发病机制中的作用尚不清楚。先前的工作表明，轴突起始段(AIS)中不存在αII血影蛋白，这对远端轴突的扩散起到了促进作用。在这里，我们已经证明了在啮齿动物和人类的躯体树突状细胞和轴突结构域中普遍表达αII血影蛋白。CRISPR介导的Sptan1基因在胚胎大鼠前脑中的缺失导致树突状和轴突发育改变，AIS丢失，抑制性神经支配减少。人EIEE5突变体SPTAN1在胚胎大鼠前脑和小鼠海马神经元中过表达导致类似的发育缺陷，在EIEE5患者来源的神经元中也观察到了类似的发育缺陷。此外，患者来源的神经元显示出鬼影蛋白复合体的聚集。综上所述，这些发现暗示αII光谱蛋白在树突状细胞和轴突发育以及突触形成的关键方面，并支持EIEE5中SPTAN1突变的显性负机制。
The nonerythrocytic alpha-spectrin-1 (SPTAN1) gene encodes the cytoskeletal protein alpha II spectrin. Mutations in SPTAN1 cause early infantile epileptic encephalopathy type 5 (EIEE5); however, the role of alpha II spectrin in neurodevelopment and EIEE5 pathogenesis is unknown. Prior work suggests that alpha II spectrin is absent in the axon initial segment (AIS) and contributes to a diffusion barrier in the distal axon. Here, we have shown that alpha II spectrin is expressed ubiquitously in rodent and human somatodendritic and axonal domains. CRISPR-mediated deletion of Sptan1 in embryonic rat forebrain by in utero electroporation caused altered dendritic and axonal development, loss of the AIS, and decreased inhibitory innervation. Overexpression of human EIEE5 mutant SPTAN1 in embryonic rat forebrain and mouse hippocampal neurons led to similar developmental defects that were also observed in EIEE5 patient-derived neurons. Additionally, patient-derived neurons displayed aggregation of spectrin complexes. Taken together, these findings implicate alpha II spectrin in critical aspects of dendritic and axonal development and synaptogenesis, and support a dominant-negative mechanism of SPTAN1 mutations in EIEE5.