Université Paris-Saclay, INSERM U1204, Univ Evry, Structure-Activité des Biomolécules Normales et Pathologiques (SABNP), Evry-Courcouronnes, France.
SYNSIGHT, Evry-Courcouronnes, France.
Elife. 2021 Sep 7;10:e67605. doi: 10.7554/eLife.67605.
TDP-43 is a nuclear RNA-binding protein that forms neuronal cytoplasmic inclusions in two major neurodegenerative diseases, ALS and FTLD. While the self-assembly of TDP-43 by its structured N-terminal and intrinsically disordered C-terminal domains has been widely studied, the mechanism by which mRNA preserves TDP-43 solubility in the nucleus has not been addressed. Here, we demonstrate that tandem RNA recognition motifs of TDP-43 bind to long GU-repeats in a cooperative manner through intermolecular interactions. Moreover, using mutants whose cooperativity is impaired, we found that the cooperative binding of TDP-43 to mRNA may be critical to maintain the solubility of TDP-43 in the nucleus and the miscibility of TDP-43 in cytoplasmic stress granules. We anticipate that the knowledge of a higher order assembly of TDP-43 on mRNA may clarify its role in intron processing and provide a means of interfering with the cytoplasmic aggregation of TDP-43.
TDP-43 是一种核 RNA 结合蛋白，在两种主要的神经退行性疾病 ALS 和额颞叶变性中形成神经元细胞质包含物。虽然 TDP-43 的结构 N 端和固有无序 C 端结构域的自组装已被广泛研究，但保持 TDP-43 在核内可溶性的 mRNA 机制尚未解决。在这里，我们证明 TDP-43 的串联 RNA 识别基序通过分子间相互作用以协同方式结合到长 GU 重复序列上。此外，使用协同性受损的突变体，我们发现 TDP-43 与 mRNA 的协同结合对于维持 TDP-43 在核内的可溶性和细胞质应激颗粒中的混合性可能至关重要。我们预计，对 TDP-43 在 mRNA 上的更高阶组装的了解可能会阐明其在内含子加工中的作用，并提供一种干扰 TDP-43 细胞质聚集的方法。
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