Selective occurrence of TDP-43-immunoreactive inclusions in the lower motor neurons in Machado-Joseph disease
Selective occurrence of TDP-43-immunoreactive inclusions in the lower motor neurons in Machado-Joseph disease
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DOI：
10.1007/s00401-009-0552-x
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发表时间：
2009-10-01
影响因子：
12.7
通讯作者：
Takahashi, Hitoshi
中科院分区：
文献类型：
--
作者：
Tan, Chun-Feng;Yamada, Mitsunori;Takahashi, Hitoshi
病理性反式激活反应性 DNA 结合蛋白 43 (TDP-43) 已被确定为运动神经元疾病额颞叶变性以及散发性和某些形式的家族性肌萎缩侧索硬化症中泛素化包涵体的组成部分。为了阐明病理性 TDP-43 是否存在于涉及运动神经元系统的其他神经退行性疾病中，我们使用针对 TDP-43 的多克隆抗体，对受两种 CAG 重复（聚谷氨酰胺）疾病（马查多-约瑟夫病 (MJD) 和脊髓和延髓肌萎缩症 (SBMA)）影响的大脑和脊髓进行了免疫组织化学检查。在所有 MJD 病例中，TDP-43 免疫反应性 (ir) 神经元细胞质内含物 (NCI) 虽然数量很少，但仅在脑干和脊髓的下运动神经元中发现。 TDP-43-ir NCI 表现为线性的缕状、绞状或粗的、有点棒状的物体。这些内含物也可以用抗 TDP-43 磷酸丝氨酸 409 和 410 以及泛素的抗体可视化，但不能被抗扩展聚谷氨酰胺片段或 ataxin-3 的抗体识别。 TDP-43-ir NCI 的超微结构与零星 ALS 中所见的内含物相似，由平行丝束组成。 SBMA 病例在任何检查区域均未表现出异常 TDP-43 免疫反应性。在所检查的两例 MJD 病例中，免疫印迹分析未能识别出类似 23 kDa 的过度磷酸化 TDP-43。然而，免疫组织化学结果强烈表明，在 MJD 中，除了多谷氨酰胺依赖性疾病过程外，TDP-43 相关的发病机制还与下运动神经元的变性和死亡有关。
Pathological transactivation-responsive DNA-binding protein 43 (TDP-43) has been identified as a component of ubiquitinated inclusions in frontotemporal lobar degeneration with motor neuron disease, as well as in sporadic and some forms of familial amyotrophic lateral sclerosis. To clarify whether pathological TDP-43 is present in other neurodegenerative diseases involving the motor neuron system, we immunohistochemically examined the brain and spinal cord affected by two CAG repeat (polyglutamine) diseases, Machado-Joseph disease (MJD) and spinal and bulbar muscular atrophy (SBMA), using polyclonal antibody against TDP-43. In all the MJD cases, TDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs), although few in number, were found only in the lower motor neurons in the brainstem and spinal cord. TDP-43-ir NCIs appeared as linear wisp-like, skein-like, or thick, somewhat rod-like bodies. These inclusions were also visualized with antibodies against phosphoserines 409 and 410 of TDP-43, and ubiquitin, but were not recognized by antibody against expanded polyglutamine stretches or ataxin-3. The ultrastructure of the TDP-43-ir NCIs was similar to that of the inclusions seen in sporadic ALS, consisting of bundles of parallel filaments. None of the SBMA cases showed abnormal TDP-43 immunoreactivity in any of the regions examined. Immunoblot analysis failed to recognize hyperphosphorylated TDP-43 at similar to 23 kDa in two MJD cases examined. However, the immunohistochemical findings strongly suggested that in MJD, in addition to the polyglutamine-dependent disease process, TDP-43-related pathogenesis is associated with degeneration and death of the lower motor neurons.