Department of Neurology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
Neurosci Lett. 2010 Jul 5;478(2):72-6. doi: 10.1016/j.neulet.2010.04.068. Epub 2010 May 4.
TDP-43 is ubiquitously expressed in the nucleus of motor neurons and is closely associated with the pathogenesis of amyotrophic lateral sclerosis (ALS). However, little is known about alterations in the subcellular or intracellular localization of TDP-43, either under normal conditions or in ALS. We examined the anterior horn neurons of the spinal cord in patients with sporadic ALS and age-matched controls immunohistochemically and immunoelectron-microscopically using anti-TDP-43 antibody. Immunohistochemically, the present study showed a decrease in TDP-43 immmunoreactivity in the nucleus and, by contrast, an increase in the cytoplasm in ALS patients. Immunoelectron-microscopically, we demonstrated the consistent presence of TDP-43-immunogold-labeled deposits primarily in the nucleus, particularly in the nucleolus, and frequently in the rough endoplasmic reticulum (rER), and, to a lesser extent, in the mitochondria and the synaptic vesicles of the presynaptic terminals on the surface of anterior horn neurons both in controls and ALS subjects. In ALS, a reduced number of TDP-43-immunogold-labeled deposits were observed in the nuclei, particularly in the nucleoli of even normal-looking motor neurons. In contrast, the number of TDP-43-immunogold-labeled deposits in the rER of the normal-appearing motor neurons was significantly larger in ALS than in the controls (p=0.0036). These findings suggest that TDP-43 is synthesized in the rER and translocates to the nucleus, particularly to the nucleolus, and in ALS, TDP-43 trafficking between the nucleus and the cytoplasm is disturbed, resulting in an accumulation of TDP-43 in the cytoplasm in the form of insoluble aggregates.
TDP-43 在运动神经元的核内广泛表达，与肌萎缩侧索硬化症（ALS）的发病机制密切相关。然而，在正常情况下或在 ALS 中，TDP-43 的亚细胞或细胞内定位的改变知之甚少。我们使用抗 TDP-43 抗体对散发性 ALS 患者和年龄匹配的对照组的脊髓前角神经元进行了免疫组织化学和免疫电镜检查。免疫组织化学显示，本研究显示 ALS 患者的核内 TDP-43 免疫反应性降低，而细胞质内 TDP-43 免疫反应性增加。免疫电镜显示，我们在对照组和 ALS 患者的前角神经元表面的核内，特别是在核仁内，经常在粗面内质网（rER）中，并且在较小程度上在线粒体和突触小泡中，一致存在 TDP-43-免疫金标记沉积物。在 ALS 中，观察到核内 TDP-43-免疫金标记沉积物的数量减少，特别是在即使外观正常的运动神经元的核仁中。相比之下，在正常外观的运动神经元的 rER 中，TDP-43-免疫金标记沉积物的数量在 ALS 中明显大于对照组（p=0.0036）。这些发现表明 TDP-43 在 rER 中合成，并易位到核内，特别是核仁，并且在 ALS 中，核与细胞质之间的 TDP-43 运输受到干扰，导致 TDP-43 以不溶性聚集体的形式在细胞质中积累。
