An Intramolecular Salt Bridge Linking TDP43 RNA Binding, Protein Stability, and TDP43-Dependent Neurodegeneration
An Intramolecular Salt Bridge Linking TDP43 RNA Binding, Protein Stability, and TDP43-Dependent Neurodegeneration
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DOI：
10.1016/j.celrep.2019.03.093
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发表时间：
2019-04-23
期刊：
影响因子：
8.8
通讯作者：
Barmada, Sami J.
中科院分区：
文献类型：
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作者：
Flores, Brittany N.;Li, Xingli;Barmada, Sami J.
大多数患有肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）的个体表现出富含RNA结合蛋白TDP 43的神经元细胞质内含物。即便如此，TDP 43的RNA结合特性与神经变性之间的关系仍然不清楚。在这里，我们表明，工程突变破坏TDP 43的RNA识别基序之间的盐桥干扰RNA结合，并消除了对天然TDP 43底物的识别。相同的突变显著地使TDP 43不稳定，改变其亚细胞定位，并消除TDP 43依赖性神经变性。携带同源TDP-1突变的蠕虫表型敲除菌株，证实盐桥残基对于TDP 43功能的必要性。此外，功能性TDP 43的积累，而不是RNA结合缺陷的变体，不成比例地影响编码核糖体和氧化磷酸化组分的转录物。这些研究证明了盐桥在维持TDP 43稳定性和RNA结合特性方面的重要性，这些因素对于ALS和FTD中TDP 43沉积引起的神经变性至关重要。
The majority of individuals with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) exhibit neuronal cytoplasmic inclusions rich in the RNA binding protein TDP43. Even so, the relation between the RNA binding properties of TDP43 and neurodegeneration remains obscure. Here, we show that engineered mutations disrupting a salt bridge between the RNA recognition motifs of TDP43 interfere with RNA binding and eliminate the recognition of native TDP43 substrates. The same mutations dramatically destabilize TDP43, alter its subcellular localization, and abrogate TDP43-dependent neurodegeneration. Worms harboring homologous TDP-1 mutations phenocopy knockout strains, confirming the necessity of salt bridge residues for TDP43 function. Moreover, the accumulation of functional TDP43, but not RNA binding-deficient variants, disproportionately affects transcripts encoding ribosome and oxidative phosphorylation components. These studies demonstrate the significance of the salt bridge in sustaining TDP43 stability and RNA binding properties, factors that are crucial for neurodegeneration arising from TDP43 deposition in ALS and FTD.