化学
单体
生物物理学
蛋白质聚集
计算生物学
原籍国
肌萎缩侧索硬化
纤维
寡核苷酸
生物化学
DNA
组合化学
生物
医学
疾病
有机化学
聚合物
病理
作者
Lijun Yang,Yllza Jasiqi,Agnès Zettor,Oscar Vadas,Jeanne Chiaravalli,Fabrice Agou,Hilal A. Lashuel
标识
DOI:10.1002/ange.202314587
摘要
Abstract Preventing the misfolding or aggregation of transactive response DNA binding protein with 43 kDa (TDP‐43) is the most actively pursued disease‐modifying strategy to treat amyotrophic lateral sclerosis and other neurodegenerative diseases. In this work, we provide proof of concept that native state stabilization of TDP‐43 is a viable and effective strategy for treating TDP‐43 proteinopathies. Firstly, we leveraged the Cryo‐EM structures of TDP‐43 fibrils to design C‐terminal substitutions that disrupt TDP‐43 aggregation. Secondly, we showed that these substitutions (S333D/S342D) stabilize monomeric TDP‐43 without altering its physiological properties. Thirdly, we demonstrated that binding native oligonucleotide ligands stabilized monomeric TDP‐43 and prevented its fibrillization and phase separation in the absence of direct binding to the aggregation‐prone C‐terminal domain. Fourthly, we showed that the monomeric TDP‐43 variant could be induced to aggregate in a controlled manner, which enabled the design and implementation of a high‐throughput screening assay to identify native state stabilizers of TDP‐43. Altogether, our findings demonstrate that different structural domains in TDP‐43 could be exploited and targeted to develop drugs that stabilize the native state of TDP‐43 and provide a platform to discover novel drugs to treat TDP‐43 proteinopathies.
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