Interaction with Polyglutamine Aggregates Reveals a Q/N-rich Domain in TDP-43
Interaction with Polyglutamine Aggregates Reveals a Q/N-rich Domain in TDP-43
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DOI：
10.1074/jbc.m110.125039
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发表时间：
2010-08-20
影响因子：
4.8
通讯作者：
Baloh, Robert H.
中科院分区：
文献类型：
--
作者：
Fuentealba, Rodrigo A.;Udan, Maria;Baloh, Robert H.
肌萎缩侧索硬化症 (ALS) 和额颞叶变性中病理性 TDP-43 聚集体的鉴定，以及家族性 ALS 中 TDP-43 显性遗传点突变的发现，为了解这些无法治疗的神经退行性疾病的机制提供了重要的见解。然而，TDP-43聚集的生化基础以及TDP-43突变如何导致疾病的机制仍然是个谜。在努力了解 TDP-43 如何改变其细胞定位以响应蛋白毒性应激时，我们发现 TDP-43 被隔离在聚谷氨酰胺聚集体中。此外，我们发现与聚谷氨酰胺聚集体的结合需要 TDP-43 C 端结构域中先前未表征的谷氨酰胺/天冬酰胺 (Q/N) 丰富区域。螯合到聚谷氨酰胺聚集体中会导致 TDP-43 从细胞核中清除，并变得不溶于洗涤剂。最后，我们观察到多聚谷氨酰胺聚集体的隔离导致细胞核中 TDP-43 介导的剪接丧失，并且多聚谷氨酰胺毒性可以通过增加 TDP-43 的表达来部分缓解。这些数据表明多聚谷氨酰胺聚集体的病理性隔离以及核 TDP-43 功能的丧失可能在多聚谷氨酰胺疾病的发病机制中发挥意想不到的作用。此外，由于 Q/N 结构域具有强烈的自我聚集倾向，并且在某些情况下可以充当朊病毒，因此 TDP-43 中 Q/N 结构域的识别对于 TDP-43 在 ALS 和其他神经退行性疾病中的病理聚集机制具有重要意义。
The identification of pathologic TDP-43 aggregates in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, followed by the discovery of dominantly inherited point mutations in TDP-43 in familial ALS, have been critical insights into the mechanism of these untreatable neurodegenerative diseases. However, the biochemical basis of TDP-43 aggregation and the mechanism of how mutations in TDP-43 lead to disease remain enigmatic. In efforts to understand how TDP-43 alters its cellular localization in response to proteotoxic stress, we found that TDP-43 is sequestered into polyglutamine aggregates. Furthermore, we found that binding to polyglutamine aggregates requires a previously uncharacterized glutamine/asparagine (Q/N)-rich region in the C-terminal domain of TDP-43. Sequestration into polyglutamine aggregates causes TDP-43 to be cleared from the nucleus and become detergent-insoluble. Finally, we observed that sequestration into polyglutamine aggregates led to loss of TDP-43-mediated splicing in the nucleus and that polyglutamine toxicity could be partially rescued by increasing expression of TDP-43. These data indicate pathologic sequestration into polyglutamine aggregates, and loss of nuclear TDP-43 function may play an unexpected role in polyglutamine disease pathogenesis. Furthermore, as Q/N domains have a strong tendency to self-aggregate and in some cases can function as prions, the identification of a Q/N domain in TDP-43 has important implications for the mechanism of pathologic aggregation of TDP-43 in ALS and other neurodegenerative diseases.