Onozato T, Nakahara A, Suzuki-Kouyama E, Hineno A, Yasude T, Nakamura T, Yahikozawa H, Watanabe M, Kayanuma K, Makishita H, Ohara S, Hashimoto T, Higuchi K, Sakai T, Asano K, Hashimoto T, Kanno H, Nakayama J, Oyanagi K
Division of Neuropathology, Department of Brain Disease Research, Shinshu University School of Medicine, Nagano, Japan.
Safety Research Laboratory of Research and Development, Kissei Pharmaceutical Co., Ltd., Nagano, Japan.
Neuropathol Appl Neurobiol. 2016 Oct;42(6):561-72. doi: 10.1111/nan.12310. Epub 2016 Mar 22.
Axonal aggregates of phosphorylated (p-) transactive response DNA-binding protein 43 kDa (TDP-43) in sporadic amyotrophic lateral sclerosis (sALS) were examined in relation to propagation of the protein in the nervous system.
Brains and spinal cords of Japanese patients with sALS and control subjects were examined immunohistochemically using formalin-fixed paraffin-embedded specimens with special reference to the topographical distribution, microscopic features, presynaptic aggregates, and correlation between the aggregates in axons and the clinical course.
(i) Aggregates of p-TDP-43 were frequently present in axons of the hypoglossal and facial nerve fibres and the spinal anterior horn cells. (ii) Aggregates of p-TDP-43 in the axons showed two characteristic microscopic features - dash-like granuloreticular aggregates (GRAs) and massive aggregates (MAs). (iii) MAs were surrounded by p-neurofilaments, but p-neurofilament immunnoreactivity decreased at the inside of axons with GRAs. (iv) Patients showing MAs and GRAs had a relatively shorter clinical course than patients without the aggregates. (v) Some neurones in the red nucleus in patients were surrounded by synapses containing p- and p-independent (i)-TDP-43, and almost all neurones had lost their nuclear TDP-43 immunoreactivity; 17% of those neurones in the red nucleus also had TDP-43-immunopositive neuronal cytoplasmic inclusions, but no postsynaptic p-TDP-43 deposition was evident.
There are two types of axonal p-TDP-43 aggregates, MAs and GRAs, located predominantly in the facial and hypoglossal nuclei and anterior horn cells. These aggregates may influence the function of neurones, and presynaptic aggregates of the protein induce loss of p-i-TDP-43 in the nuclei of postsynaptic neurones.
研究散发性肌萎缩侧索硬化症（sALS）中磷酸化（p-）反式激活反应DNA结合蛋白43 kDa（TDP-43）的轴突聚集体与该蛋白在神经系统中的传播情况。
对日本sALS患者和对照者的脑和脊髓进行免疫组织化学检查，使用福尔马林固定石蜡包埋标本，特别关注其地形分布、微观特征、突触前聚集体以及轴突聚集体与临床病程之间的相关性。
（i）p-TDP-43聚集体常见于舌下神经和面神经纤维的轴突以及脊髓前角细胞中。（ii）轴突中的p-TDP-43聚集体呈现出两种特征性微观特征——短划线样颗粒网状聚集体（GRAs）和大量聚集体（MAs）。（iii）MAs被p-神经丝包围，但在含有GRAs的轴突内部，p-神经丝免疫反应性降低。（iv）出现MAs和GRAs的患者临床病程相对较短，而没有聚集体的患者临床病程较长。（v）患者红核中的一些神经元被含有p-TDP-43和非p-依赖性（i）-TDP-43的突触包围，几乎所有神经元都失去了核TDP-43免疫反应性；红核中17%的神经元也有TDP-43免疫阳性的神经元胞质内包涵体，但突触后p-TDP-43沉积不明显。
存在两种类型的轴突p-TDP-43聚集体，即MAs和GRAs，主要位于面神经核、舌下神经核和前角细胞中。这些聚集体可能影响神经元的功能，并且该蛋白的突触前聚集体会导致突触后神经元细胞核中p-i-TDP-43的丢失。
