Cell stress induces TDP-43 pathological changes associated with ERK1/2 dysfunction: implications in ALS
Cell stress induces TDP-43 pathological changes associated with ERK1/2 dysfunction: implications in ALS
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DOI：
10.1007/s00401-011-0850-y
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发表时间：
2011-09-01
影响因子：
12.7
通讯作者：
Portero-Otin, Manuel
中科院分区：
文献类型：
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作者：
Ayala, Victoria;Belen Granado-Serrano, Ana;Portero-Otin, Manuel
TDP-43与肌萎缩性侧索硬化症和其他神经退行性疾病的发病机制有关。在这里，我们利用神经元和脊髓器官型培养模型证明，慢性兴奋毒性、氧化应激、蛋白酶体功能障碍和内质网应激机制诱导了TDP-43的错误定位、磷酸化和聚集。这与细胞核中缺乏这种蛋白质的功能是一致的，特别是在运动神经元中。细胞应激与TDP-43病理变化之间的关系还包括丝裂原活化蛋白激酶/细胞外信号调节激酶（ERK1/2）介导的存活途径功能障碍。因此，在应激条件下，神经元和其他脊髓细胞显示含有ERK1/2的胞质聚集体。此外，在肌萎缩性侧索硬化症（ALS）的脊髓中也发现了异常磷酸化的ERK1/2聚集物，特别是在磷酸化TDP-43免疫反应性聚集物异常的运动神经元中。这些结果表明，细胞应激源是与TDP-43相关的神经退行性变的关键因素，并揭示了ERK1/2在ALS发病机制中的新角色。
TDP-43 has been implicated in the pathogenesis of amyotrophic lateral sclerosis and other neurodegenerative diseases. Here we demonstrate, using neuronal and spinal cord organotypic culture models, that chronic excitotoxicity, oxidative stress, proteasome dysfunction and endoplasmic reticulum stress mechanistically induce mislocalization, phosphorylation and aggregation of TDP-43. This is compatible with a lack of function of this protein in the nucleus, specially in motor neurons. The relationship between cell stress and pathological changes of TDP-43 also includes a dysfunction in the survival pathway mediated by mitogen-activated protein kinase/extracellular signal-regulated kinases (ERK1/2). Thus, under stress conditions, neurons and other spinal cord cells showed cytosolic aggregates containing ERK1/2. Moreover, aggregates of abnormal phosphorylated ERK1/2 were also found in the spinal cord in amyotrophic lateral sclerosis (ALS), specifically in motor neurons with abnormal immunoreactive aggregates of phosphorylated TDP-43. These results demonstrate that cellular stressors are key factors in neurodegeneration associated with TDP-43 and disclose the identity of ERK1/2 as novel players in the pathogenesis of ALS.