Altered immunoreactivity of ErbB4, a causative gene product for ALS19, in the spinal cord of patients with sporadic ALS
Altered immunoreactivity of ErbB4, a causative gene product for ALS19, in the spinal cord of patients with sporadic ALS
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DOI：
10.1111/neup.12558
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发表时间：
2019-08-01
期刊：
影响因子：
2.3
通讯作者：
Saito, Yuko
中科院分区：
文献类型：
--
作者：
Takahashi, Yuji;Uchino, Akiko;Saito, Yuko
ErbB4是一种与家族性肌萎缩侧索硬化症（ALS）相关的蛋白质，被命名为ALS19。ErbB4是一种受体酪氨酸激酶，可被其配体神经调节蛋白（NRG）激活，在运动神经元的功能和存活中起着至关重要的作用。ALS19基因的突变导致ErbB4蛋白在受到NRG - 1刺激时自身磷酸化能力降低，这表明NRG - ErbB4通路的破坏会导致运动神经元变性。我们利用免疫组织化学方法研究散发性肌萎缩侧索硬化症（SALS）患者脊髓中的ErbB4，以验证ErbB4可能参与SALS发病机制的假设。ErbB4在脊髓前角运动神经元的细胞质中呈特异性免疫反应。在SALS患者中，一些运动神经元失去了对ErbB4的免疫反应性，且失去免疫反应性的运动神经元比例与运动神经元丢失的严重程度相关。其亚细胞定位发生改变，表现为核仁或核定位、条索/点状和球状。观察到异位的神经胶质免疫反应性，主要在侧柱和前角的少突胶质细胞中。ErbB4免疫反应性的降低与运动神经元中转录激活反应DNA结合蛋白43 kDa（TDP - 43）的细胞质错误定位显著相关。在携带超氧化物歧化酶1基因（SOD1）突变形式转基因的小鼠运动神经元中未观察到免疫反应性的改变。这项研究提供了令人信服的证据，表明ErbB4也参与了SALS的病理生理学过程，并且NRG - ErbB4通路的破坏可能是ALS中依赖于TDP - 43的运动神经元变性的基础。
ErbB4 is the protein implicated in familial amyotrophic lateral sclerosis (ALS), designated as ALS19. ErbB4 is a receptor tyrosine kinase activated by its ligands, neuregulins (NRG), and plays an essential role in the function and viability of motor neurons. Mutations in the ALS19 gene lead to the reduced autophosphorylation capacity of the ErbB4 protein upon stimulation with NRG-1, suggesting that the disruption of the NRG-ErbB4 pathway causes motor neuron degeneration. We used immunohistochemistry to study ErbB4 in the spinal cord of patients with sporadic ALS (SALS) to test the hypothesis that ErbB4 may be involved in the pathogenesis of SALS. ErbB4 was specifically immunoreactive in the cytoplasm of motor neurons in the anterior horns of the spinal cord. In patients with SALS, some of the motor neurons lost immunoreactivity with ErbB4, with the proportion of motor neurons with a loss of immunoreactivity correlated with the severity of motor neuron loss. The subcellular localization was altered, demonstrating nucleolar or nuclear localization, threads/dots and spheroids. The ectopic glial immunoreactivity was observed, mainly in the oligodendrocytes of the lateral columns and anterior horns. The reduction in the ErbB4 immunoreactivity was significantly correlated with the cytoplasmic mislocalization of transactivation response DNA-binding protein 43 kDa (TDP-43) in the motor neurons. No alteration in immunoreactivity was observed in the motor neurons of mice carrying atransgene for mutant form of the superoxide dismutase 1 gene (SOD1). This study provided compelling evidence that ErbB4 is also involved in the pathophysiology of SALS, and that the disruption of the NRG-ErbB4 pathway may underlie the TDP-43-dependent motor neuron degeneration in ALS.