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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...

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Autores principales: Gao, Ju, Wang, Luwen, Ren, Xiaojia, Dunn, Justin R., Peters, Ariele, Miyagi, Masaru, Fujioka, Hisashi, Zhao, Fangli, Askwith, Candice, Liang, Jingjing, Wang, Xinglong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2021
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.
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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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