Stress induces dynamic, cytotoxicity-antagonizing TDP-43 nuclear bodies via paraspeckle lncRNA NEAT1 -mediated liquid-liquid phase separation
Stress induces dynamic, cytotoxicity-antagonizing TDP-43 nuclear bodies via paraspeckle lncRNA NEAT1 -mediated liquid-liquid phase separation
Graphic Abstractbiorxiv;802058v2/UFIG1F1ufig1 Highlights(Up to four bullet points. The length of each highlight cannot exceed 85 characters, including spaces)Stress induces phase-separated TDP-43 NBs to alleviate cytotoxicityThe two RRMs interact with different RNAs and act distinctly in the assembly of TDP-43 NBsLncRNA NEAT1 promotes TDP-43 LLPS and is upregulated in stressed neuronsThe ALS-causing D169G mutation is NB-defective and forms pTDP-43 cytoplasmic foci SummaryDespite the prominent role of TDP-43 in neurodegeneration, its physiological and pathological functions are not fully understood. Here, we report an unexpected function of TDP-43 in the formation of dynamic, reversible, liquid droplet-like nuclear bodies (NBs) in response to stress. Formation of NBs alleviates TDP-43-mediated cytotoxicity in mammalian cells and fly neurons. Super-resolution microscopy reveals a “core-shell” organization of TDP-43 NBs, antagonistically maintained by the two RRMs. TDP-43 NBs are partially colocalized with nuclear paraspeckles, whose scaffolding lncRNA NEAT1 is dramatically upregulated in stressed neurons. Moreover, increase of NEAT1 promotes TDP-43 liquid-liquid phase separation (LLPS) in vitro. Finally, we uncover that the ALS-associated mutation D169G impairs the NEAT1-mediated TDP-43 LLPS and NB assembly, causing excessive cytoplasmic translocation of TDP-43 to form stress granules that become phosphorylated TDP-43 cytoplasmic foci upon prolonged stress. Together, our findings suggest a stress-mitigating role and mechanism of TDP-43 NBs, whose dysfunction may be involved in ALS pathogenesis.
Duan Gang、Wang Chen、Ma Zhiwei、Guo Lin、Fang Yanshan、Deng Xue、Qian Beituo、Zhang Shuang、Gu Jinge、Wang Qiangqiang、Zhang Kai、Duan Yongjia、Liu Cong
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences||2University of Chinese Academy of SciencesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences||2University of Chinese Academy of SciencesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of SciencesDepartment of Biochemistry and Molecular Biology, Thomas Jefferson University,Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences||2University of Chinese Academy of SciencesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences||2University of Chinese Academy of SciencesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences||2University of Chinese Academy of SciencesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of SciencesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences||2University of Chinese Academy of SciencesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of SciencesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences||2University of Chinese Academy of SciencesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences||2University of Chinese Academy of SciencesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences||2University of Chinese Academy of Sciences
神经病学、精神病学基础医学分子生物学
TDP-43nuclear bodyphase separationlncRNA NEAT1ALS
Duan Gang,Wang Chen,Ma Zhiwei,Guo Lin,Fang Yanshan,Deng Xue,Qian Beituo,Zhang Shuang,Gu Jinge,Wang Qiangqiang,Zhang Kai,Duan Yongjia,Liu Cong.Stress induces dynamic, cytotoxicity-antagonizing TDP-43 nuclear bodies via paraspeckle lncRNA NEAT1 -mediated liquid-liquid phase separation[EB/OL].(2025-03-28)[2025-07-01].https://www.biorxiv.org/content/10.1101/802058.点此复制
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