Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA.
J Clin Invest. 2013 Feb;123(2):646-56. doi: 10.1172/JCI64811. Epub 2013 Jan 2.
Progressive loss of visual function frequently accompanies demyelinating diseases such as multiple sclerosis (MS) and is hypothesized to be the result of damage to the axons and soma of neurons. Here, we show that dendritic impairment is also involved in these diseases. Deimination, a posttranslational modification, was reduced in the retinal ganglion cell layer of MS patients and in a transgenic mouse model of MS (ND4 mice). Reduced deimination accompanied a decrease in inner retinal function in ND4 mice, indicating loss of vision. Local restoration of deimination dramatically improved retinal function and elongation of neurites in isolated neurons. Further, neurite length was decreased by downregulation of deimination or siRNA knockdown of the export-binding protein REF, a primary target for deimination in these cells. REF localized to dendrites and bound selective mRNAs and translation machinery to promote protein synthesis. Thus, protein deimination and dendritic outgrowth play key roles in visual function and may be a general feature of demyelinating diseases.
视觉功能的进行性丧失常伴随着脱髓鞘疾病，如多发性硬化症（MS），并被假设为神经元轴突和体的损伤的结果。在这里，我们表明树突损害也与这些疾病有关。去氨基化作用，一种翻译后修饰，在 MS 患者的视网膜神经节细胞层和 MS 的转基因小鼠模型（ND4 小鼠）中减少。ND4 小鼠中的去氨基化作用减少伴随着内视网膜功能的下降，表明视力丧失。局部恢复去氨基化作用可显著改善视网膜功能和孤立神经元中神经突的伸长。此外，去氨基化作用的下调或出口结合蛋白 REF 的 siRNA 敲低会降低神经突的长度，REF 是这些细胞中去氨基化作用的主要靶标。REF 定位于树突，并结合选择性的 mRNA 和翻译机制，以促进蛋白质合成。因此，蛋白质去氨基化和树突生长在视觉功能中起着关键作用，并且可能是脱髓鞘疾病的一个普遍特征。
