A Seeding Reaction Recapitulates Intracellular Formation of Sarkosyl-insoluble Transactivation Response Element (TAR) DNA-binding Protein-43 Inclusions
A Seeding Reaction Recapitulates Intracellular Formation of Sarkosyl-insoluble Transactivation Response Element (TAR) DNA-binding Protein-43 Inclusions
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DOI：
10.1074/jbc.m111.231209
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发表时间：
2011-05-27
影响因子：
4.8
通讯作者：
Nukina, Nobuyuki
中科院分区：
文献类型：
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作者：
Furukawa, Yoshiaki;Kaneko, Kumi;Nukina, Nobuyuki
转录激活反应元件（TAR）DNA结合蛋白-43（TDP-43）是一种核蛋白，通常调节转录和剪接。最近有报道称，肌萎缩侧索硬化症（ALS）患者的受累组织中存在含有TDP-43的不溶性内含物的异常积聚。在这里，我们表明，TDP-43的细胞内聚集可以触发由在体外功能TDP-43制备的纤维状聚集体的转导。发现肌氨酰不能溶解TDP-43的那些细胞内接种的聚集体，这与ALS患者中TDP-43包涵体是肌氨酰不溶性的观察结果一致。此外，我们的细胞模型中的细胞内接种再现了TDP-43聚集体的泛素化，这是ALS患者中TDP-43包涵体的另一个突出特征。虽然到目前为止，使用培养的细胞模型很难启动TDP-43的疾病相关变化，但我们提出接种反应是构建监测TDP-43病理的模型的关键。
The transactivation response element (TAR) DNA-binding protein-43 (TDP-43) is a nuclear protein that normally regulates transcription and splicing. Abnormal accumulation of insoluble inclusions containing TDP-43 has been recently reported in the affected tissues of amyotrophic lateral sclerosis (ALS) patients. Here, we show that intracellular aggregation of TDP-43 can be triggered by transduction of fibrillar aggregates prepared from in vitro functional TDP-43. Sarkosyl is found to be incapable of solubilizing those intracellularly seeded aggregates of TDP-43, which is consistent with the observation that TDP-43 inclusions in ALS patients are sarkosyl-insoluble. In addition, intracellular seeding in our cell models reproduces ubiquitination of TDP-43 aggregates, which is another prominent feature of TDP-43 inclusions in ALS patients. Although it has been so far difficult to initiate disease-associated changes of TDP-43 using cultured cell models, we propose that a seeding reaction is a key to construct a model to monitor TDP-43 pathologies.