The N Termini of TAR DNA-Binding Protein 43 (TDP43) C-Terminal Fragments Influence Degradation, Aggregation Propensity, and Morphology.
The N Termini of TAR DNA-Binding Protein 43 (TDP43) C-Terminal Fragments Influence Degradation, Aggregation Propensity, and Morphology.
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DOI：
10.1128/mcb.00243-18
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发表时间：
2018-10-01
影响因子：
5.3
通讯作者：
Brower CS
中科院分区：
文献类型：
--
作者：
Kasu YAT;Alemu S;Lamari A;Loew N;Brower CS
TAR DNA结合蛋白43（TDP 43）片段是肌萎缩侧索硬化和额颞叶痴呆相关的细胞内聚集体的主要成分。存在各种C-末端片段（CTF），具有不同的N末端;然而，关于它们在代谢和聚集动力学方面的差异知之甚少。TAR DNA结合蛋白43（TDP 43）片段是肌萎缩侧索硬化和额颞叶痴呆相关的细胞内聚集体的主要成分。存在各种C-末端片段（CTF），具有不同的N末端;然而，关于它们在代谢和聚集动力学方面的差异知之甚少。以前，我们发现，特定的CTF积累的情况下，精氨酸/N-末端规则途径的泛素蛋白酶体系统（UPS）和它们的降解需要乙酰基-tRNA蛋白转移酶1（ATE 1）。在这里，我们检查了TDP 43的两个特异性CTF（TDP 43219和TDP 43247），它们具有约85%的相同性，并且在它们的N末端处相差28个氨基酸。我们发现TDP 43247主要通过Arg/N-末端规则途径降解，而TDP 43219的降解在不存在ATE 1的情况下继续。这些片段在它们的聚集倾向上也不同，并形成形态上不同的聚集体。这项工作表明，其他类似的CTF的N末端对片段行为有深远的影响，并可能影响与聚集相关的神经变性的临床结果。
Fragments of the TAR DNA-binding protein 43 (TDP43) are major components of intracellular aggregates associated with amyotrophic lateral sclerosis and frontotemporal dementia. A variety of C-terminal fragments (CTFs) exist, with distinct N termini; however, little is known regarding their differences in metabolism and aggregation dynamics. Fragments of the TAR DNA-binding protein 43 (TDP43) are major components of intracellular aggregates associated with amyotrophic lateral sclerosis and frontotemporal dementia. A variety of C-terminal fragments (CTFs) exist, with distinct N termini; however, little is known regarding their differences in metabolism and aggregation dynamics. Previously, we found that specific CTFs accumulate in the absence of the Arg/N-end rule pathway of the ubiquitin proteasome system (UPS) and that their degradation requires arginyl-tRNA protein transferase 1 (ATE1). Here, we examined two specific CTFs of TDP43 (TDP43219 and TDP43247), which are ∼85% identical and differ at their N termini by 28 amino acids. We found that TDP43247 is degraded primarily by the Arg/N-end rule pathway, whereas degradation of TDP43219 continues in the absence of ATE1. These fragments also differ in their aggregation propensities and form morphologically distinct aggregates. This work reveals that the N termini of otherwise similar CTFs have profound effects on fragment behavior and may influence clinical outcomes in neurodegeneration associated with aggregation.