α-COP与生存运动神经元蛋白SMN的结合是神经元突起生长所必需的。
α-COP binding to the survival motor neuron protein SMN is required for neuronal process outgrowth.
作者信息
Li Hongxia, Custer Sara K, Gilson Timra, Hao Le Thi, Beattie Christine E, Androphy Elliot J
机构信息
Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA and.
Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA.
出版信息
Hum Mol Genet. 2015 Dec 20;24(25):7295-307. doi: 10.1093/hmg/ddv428. Epub 2015 Oct 13.
Abstract
Spinal muscular atrophy (SMA), a heritable neurodegenerative disease, results from insufficient levels of the survival motor neuron (SMN) protein. α-COP binds to SMN, linking the COPI vesicular transport pathway to SMA. Reduced levels of α-COP restricted development of neuronal processes in NSC-34 cells and primary cortical neurons. Remarkably, heterologous expression of human α-COP restored normal neurite length and morphology in SMN-depleted NSC-34 cells in vitro and zebrafish motor neurons in vivo. We identified single amino acid mutants of α-COP that selectively abrogate SMN binding, retain COPI-mediated Golgi-ER trafficking functionality, but were unable to support neurite outgrowth in cellular and zebrafish models of SMA. Taken together, these demonstrate the functional role of COPI association with the SMN protein in neuronal development.
摘要
脊髓性肌萎缩症（SMA）是一种遗传性神经退行性疾病，由生存运动神经元（SMN）蛋白水平不足所致。α-COP与SMN结合，将COP I囊泡运输途径与SMA联系起来。α-COP水平降低会限制NSC-34细胞和原代皮质神经元中神经突的发育。值得注意的是，人α-COP的异源表达在体外恢复了SMN缺失的NSC-34细胞以及在体内恢复了斑马鱼运动神经元的正常神经突长度和形态。我们鉴定出了α-COP的单氨基酸突变体，这些突变体选择性地消除了与SMN的结合，保留了COP I介导的高尔基体-内质网运输功能，但在SMA的细胞和斑马鱼模型中无法支持神经突生长。综上所述，这些结果证明了COP I与SMN蛋白的结合在神经元发育中的功能作用。
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