Translational regulation in the brain by TDP-43 phase separation
| Autor: | Candice C. Askwith, Ju Gao, Xiaojia Ren, Luwen Wang, Fang-li Zhao, Xinglong Wang, Hisashi Fujioka, Jingjing Liang, Justin Dunn, Masaru Miyagi, Ariele Peters |
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| Rok vydání: | 2021 |
| Předmět: |
Neurodegeneration
nutritional and metabolic diseases Brain Translation (biology) Endogeny Cell Biology Biology medicine.disease nervous system diseases Cell biology DNA-Binding Proteins Mice Inbred C57BL Mice In vivo mental disorders Translational regulation medicine Protein biosynthesis Animals Function (biology) Brain function |
| Zdroj: | The Journal of cell biology. 220(10) |
| ISSN: | 1540-8140 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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