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首页> 外文期刊>Neuropathology: official journal of the Japanese Society of Neuropathology >Altered immunoreactivity of ErbB4, a causative gene product for ALS19, in the spinal cord of patients with sporadic ALS
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Altered immunoreactivity of ErbB4, a causative gene product for ALS19, in the spinal cord of patients with sporadic ALS

机译：ErbB4的免疫反应性改变了散发性ALS患者脊髓中的致病基因产物的造成基因产物

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摘要

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.
机译：ERBB4是含有作为ALS19指定为ALS19的家族性肌萎缩侧硬化症（ALS）的蛋白质。 ERBB4是由其配体，Neuregulins（NRG）活化的受体酪氨酸激酶，并在运动神经元的功能和活力中起重要作用。 ALS19基因中的突变导致ERBB4蛋白在NRG-1刺激后的自磷酸化能力降低，表明NRG-ERBB4途径的破坏导致运动神经元变性。我们使用免疫组织化学研究了散发性ALS（SAL）患者脊髓中的ERBB4，以测试ERBB4可参与含硅的发病机制的假设。 ERBB4在脊髓前角的电机神经元的细胞质中特别反应。在含有Sals的患者中，一些电动机神经元与ERBB4失去了免疫反应性，其中运动神经元的比例与运动神经元损失的严重程度相关的免疫反应性。亚细胞定位被改变，展示核仁或核定位，螺纹/点和球状体。观察到异位胶质免疫反应性，主要是在侧柱和前角的oligodendrocytes中。与运动神经元中的转移响应DNA结合蛋白43kDA（TDP-43）的转移反应DNA结合蛋白43kDA（TDP-43）的细胞质错误计算显着相关。在携带阿拉乙烯的小鼠的运动神经元中未观察到免疫反应性的改变，用于突变形式的超氧化物歧化酶1基因（SOD1）。本研究提供了令人信服的证据，即ErbB4也参与了Sals的病理生理学，并且NRG-ERBB4途径的破坏可能使ALS中的TDP-43依赖性运动神经元变性提高。

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