Sporadic amyotrophic lateral sclerosis: two pathological patterns shown by analysis of distribution of TDP-43-immunoreactive neuronal and glial cytoplasmic inclusions
Sporadic amyotrophic lateral sclerosis: two pathological patterns shown by analysis of distribution of TDP-43-immunoreactive neuronal and glial cytoplasmic inclusions
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DOI：
10.1007/s00401-008-0385-z
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发表时间：
2008-08-01
影响因子：
12.7
通讯作者：
Takahashi, Hitoshi
中科院分区：
文献类型：
--
作者：
Nishihira, Yasushi;Tan, Chun-Feng;Takahashi, Hitoshi
核蛋白 43-kDa TAR DNA 结合蛋白 (TDP-43) 最近被鉴定为额颞叶变性 (FTLD-U) 和散发性肌萎缩侧索硬化症 (SALS) 中泛素化包涵体 (UI) 的组成部分。在本项使用免疫组织化学的研究中，我们使用 TDP-43 多克隆抗体检查了一系列 35 个 SALS 病例中神经系统的各个区域。 35 例病例中有 7 例病程超过 10 年，需要人工呼吸支持（ARS；持续时间：69-156 个月）。在所有病例中，TDP-43 免疫反应性 (ir) 神经元和神经胶质细胞质内含物（NCIs 和 GCI）在许多区域同时被发现，包括组织学受影响的下运动神经元核。对无 ARS 病例 (n = 28) 的 TDP-43-ir NCI 分布模式进行聚类分析，确定了两种类型（1 型，n = 16；2 型，n = 12）。 2 型与 1 型的区别在于额颞叶皮质、海马结构、新纹状体和黑质中存在 TDP-43-ir NCI，并且与痴呆显着相关。 28例中有11例显示海马齿状颗粒细胞UI，全部呈2型分布模式。 ARS 病例 (n = 7) 也分为相同类型（1 型，n = 5；2 型，n = 2）。具有 1 型分布模式的病例 (n = 21) 在存在 TDP-43-ir NCI 的大多数非运动神经元核中没有显示明显的神经元丢失，而具有 2 型分布模式的病例 (n = 14) 通常在额颞叶皮质、杏仁核和黑质中显示出明显的神经元丢失。这些发现表明，SALS 是一种多系统退行性疾病，广泛影响神经元和神经胶质细胞，具有异质的 TDP-43-ir NCI 分布模式（SALS 显示 2 型分布模式与 FTLD-U 密切相关），并且呼吸器支持的长期生存对 TDP-43 神经元分布模式没有明显影响。
A nuclear protein, 43-kDa TAR DNA-binding protein (TDP-43), was recently identified as a component of the ubiquitinated inclusions (UIs) in frontotemporal lobar degeneration (FTLD-U) and sporadic amyotrophic lateral sclerosis (SALS). In the present study using immunohistochemistry, we examined various regions of the nervous system in a series of 35 SALS cases using a polyclonal antibody against TDP-43. Seven of the 35 cases had disease durations of more than 10 years with artificial respiratory support (ARS; duration: 69-156 months). In all cases, TDP-43-immunoreactive (ir) neuronal and glial cytoplasmic inclusions (NCIs and GCIs) were found together in many regions, including the histologically affected lower motor neuron nuclei. Cluster analysis of the distribution pattern of TDP-43-ir NCIs for cases without ARS (n = 28) identified two types (type 1, n = 16; type 2, n = 12). Type 2 was distinguished from type 1 by the presence of TDP-43-ir NCIs in the frontotemporal cortex, hippocampal formation, neostriatum and substantia nigra, and was significantly associated with dementia. Eleven of the 28 cases showed UIs in the hippocampal dentate granule cells, all of which had type-2 distribution pattern. Cases with ARS (n = 7) were also classified into the same types (type 1, n = 5; type 2, n = 2). Cases having type-1 distribution pattern (n = 21) showed no evident neuronal loss in most of the non-motor neuron nuclei where TDP-43-ir NCIs were present, whereas cases having type-2 distribution pattern (n = 14) often showed evident neuronal loss in the frontotemporal cortices, amygdaloid nuclei and substantia nigra. These findings indicate that SALS is a multisystem degenerative disease widely affecting both neurons and glial cells with a heterogeneous pattern of TDP-43-ir NCI distribution (SALS showing type-2 distribution pattern being closely linked to FTLD-U), and that long-term survival supported by a respirator has no apparent influence on the TDP-43 neuronal distribution pattern.