TDP‐43 pathology in polyglutamine diseases: With reference to amyotrphic lateral sclerosis
TDP‐43 pathology in polyglutamine diseases: With reference to amyotrphic lateral sclerosis
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DOI：
10.1111/neup.12053
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发表时间：
2014-02
期刊：
影响因子：
2.3
通讯作者：
Y. Toyoshima;H. Takahashi
中科院分区：
文献类型：
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作者：
Y. Toyoshima;H. Takahashi
核蛋白反式激活反应 (TAR) DNA 结合蛋白 43 kDa (TDP-43) 是泛素额颞叶变性 (FTLD-U) 和散发性肌萎缩侧索硬化症 (SALS) 中神经元细胞质包涵体 (NCI) 的主要成分。虽然最初认为 TDP-43 病理学相对特异于 FTLD-U 和 ALS，但现在已在许多其他神经退行性疾病中检测到，包括阿尔茨海默病和帕金森病。在此类 tau 蛋白病和 α-突触核蛋白病中，TDP-43 阳性神经元细胞质内含物的发生可能与其他不同的分子病理过程相关，这些过程主要分别涉及其自身的病理蛋白 tau 和 α-突触核蛋白（继发性 TDP-43 蛋白病）。另一方面，在几种聚谷氨酰胺 (polyQ) 疾病中，TDP-43 似乎发挥着重要的病理机制作用。有趣的是，最近报道称，ataxin 2（2 型脊髓小脑共济失调的致病基因）中的中等长度的 polyQ 扩展（27-33 个 Q）是 SALS 的遗传危险因素。在此，我们通过文献综述，从TDP-43神经病理学的角度讨论ALS与polyQ疾病之间的关系。
A nuclear protein, transactivation response (TAR) DNA binding protein 43 kDa (TDP‐43), is the major component of neuronal cytoplasmic inclusions (NCIs) in frontotemporal lobar degeneration with ubiquitin inclusions (FTLD‐U) and sporadic amyotrophic lateral sclerosis (SALS). While initially thought to be relatively specific to FTLD‐U and ALS, TDP‐43 pathology has now been detected in a number of other neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. In such tauopathies and α‐synucleinopathies, occurrence of TDP‐43‐positive neuronal cytoplasmic inclusions may be associated with other distinct molecular pathologic processes primarily involving their own pathological proteins, tau and α–synuclein, respectively (secondary TDP‐43 proteinopathies). On the other hand, in several polyglutamine (polyQ) diseases, TDP‐43 appears to play an important pathomechanistic role. Interestingly, intermediate‐length polyQ expansions (27–33 Qs) in ataxin 2, the causative gene of spinocerebellar ataxia type 2, have recently been reported to be a genetic risk factor for SALS. Here, with a review of the literature, we discuss the relationship between ALS and polyQ diseases from the viewpoint of TDP‐43 neuropathology.