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Translational regulation in the brain by TDP-43 phase separation
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. He...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404466/ https://www.ncbi.nlm.nih.gov/pubmed/34427634 http://dx.doi.org/10.1083/jcb.202101019 |
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author | Gao, Ju Wang, Luwen Ren, Xiaojia Dunn, Justin R. Peters, Ariele Miyagi, Masaru Fujioka, Hisashi Zhao, Fangli Askwith, Candice Liang, Jingjing Wang, Xinglong |
author_facet | Gao, Ju Wang, Luwen Ren, Xiaojia Dunn, Justin R. Peters, Ariele Miyagi, Masaru Fujioka, Hisashi Zhao, Fangli Askwith, Candice Liang, Jingjing Wang, Xinglong |
author_sort | Gao, Ju |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8404466 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-84044662022-04-04 Translational regulation in the brain by TDP-43 phase separation Gao, Ju Wang, Luwen Ren, Xiaojia Dunn, Justin R. Peters, Ariele Miyagi, Masaru Fujioka, Hisashi Zhao, Fangli Askwith, Candice Liang, Jingjing Wang, Xinglong J Cell Biol Article 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. Rockefeller University Press 2021-08-24 /pmc/articles/PMC8404466/ /pubmed/34427634 http://dx.doi.org/10.1083/jcb.202101019 Text en © 2021 Gao et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article Gao, Ju Wang, Luwen Ren, Xiaojia Dunn, Justin R. Peters, Ariele Miyagi, Masaru Fujioka, Hisashi Zhao, Fangli Askwith, Candice Liang, Jingjing Wang, Xinglong Translational regulation in the brain by TDP-43 phase separation |
title | Translational regulation in the brain by TDP-43 phase separation |
title_full | Translational regulation in the brain by TDP-43 phase separation |
title_fullStr | Translational regulation in the brain by TDP-43 phase separation |
title_full_unstemmed | Translational regulation in the brain by TDP-43 phase separation |
title_short | Translational regulation in the brain by TDP-43 phase separation |
title_sort | translational regulation in the brain by tdp-43 phase separation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404466/ https://www.ncbi.nlm.nih.gov/pubmed/34427634 http://dx.doi.org/10.1083/jcb.202101019 |
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