Translational regulation in the brain by TDP-43 phase separation |
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| Authors: | Ju Gao Luwen Wang Xiaojia Ren Justin R Dunn Ariele Peters Masaru Miyagi Hisashi Fujioka Fangli Zhao Candice Askwith Jingjing Liang Xinglong Wang |
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| Institution: | 1. Department of Pharmacology and Experimental Neurosciences, University of Nebraska Medical Center, Omaha, NE ; 2. Department of Pharmacology, Case Western Reserve University, Cleveland, OH ; 3. Electron Microscopy Core Facility, Case Western Reserve University, Cleveland, OH ; 4. Department of Neuroscience, The Ohio State University, Columbus, OH ; 5. Department of Pathology, Case Western Reserve University, Cleveland, OH |
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| Abstract: | 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. |
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