Translational regulation in the brain by TDP-43 phase separation

作者：Ju Gao, Luwen Wang, Xiaojia Ren, Justin Dunn, Ariele Peters, Masaru Miyagi, Hisashi Fujioka, Fangli Zhao, Candice C. Askwith, Jingjing Liang, Xinglong Wang · 发表于：The Journal of Cell Biology · 年份：2021 · DOI：10.1083/jcb.202101019 · 被引用次数：40 · 研究领域：RNA Research and Splicing、RNA modifications and cancer、Nuclear Structure and Function

The in vivo physiological function of liquid-liquid phase separation (LLPS) that governs non-membrane-bound structures remains elusive. Among LLPS-prone proteins, TAR DNA-binding protein of 43 kD (TDP-43) is under intense investigation because of its close association with neurological disorders. Here, we generated mice expressing endogenous LLPS-deficient murine TDP-43. LLPS-deficient TDP-43 mice demonstrate impaired neuronal function and behavioral abnormalities specifically related to brain function. Brain neurons of these mice, however, did not show TDP-43 proteinopathy or neurodegeneration. Instead, the global rate of protein synthesis was found to be greatly enhanced by TDP-43 LLPS loss. Mechanistically, TDP-43 LLPS ablation increased its association with PABPC4, RPS6, RPL7, and other translational factors. The physical interactions between TDP-43 and translational factors relies on a motif, the deletion of which abolished the impact of LLPS-deficient TDP-43 on translation. Our findings show a specific physiological role for TDP-43 LLPS in the regulation of brain function and uncover an intriguing novel molecular mechanism of translational control by LLPS.