Disease‐linked TDP‐43 hyperphosphorylation suppresses TDP‐43 condensation and aggregation

Post‐translational modifications (PTMs) have emerged as key modulators of protein phase separation and have been linked to protein aggregation in neurodegenerative disorders. The major aggregating protein in amyotrophic lateral sclerosis and frontotemporal dementia, the RNA‐binding protein TAR DNA‐b...

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Autores principales: Gruijs da Silva, Lara A, Simonetti, Francesca, Hutten, Saskia, Riemenschneider, Henrick, Sternburg, Erin L, Pietrek, Lisa M, Gebel, Jakob, Dötsch, Volker, Edbauer, Dieter, Hummer, Gerhard, Stelzl, Lukas S, Dormann, Dorothee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9016352/
https://www.ncbi.nlm.nih.gov/pubmed/35112738
http://dx.doi.org/10.15252/embj.2021108443
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author Gruijs da Silva, Lara A
Simonetti, Francesca
Hutten, Saskia
Riemenschneider, Henrick
Sternburg, Erin L
Pietrek, Lisa M
Gebel, Jakob
Dötsch, Volker
Edbauer, Dieter
Hummer, Gerhard
Stelzl, Lukas S
Dormann, Dorothee
author_facet Gruijs da Silva, Lara A
Simonetti, Francesca
Hutten, Saskia
Riemenschneider, Henrick
Sternburg, Erin L
Pietrek, Lisa M
Gebel, Jakob
Dötsch, Volker
Edbauer, Dieter
Hummer, Gerhard
Stelzl, Lukas S
Dormann, Dorothee
author_sort Gruijs da Silva, Lara A
collection PubMed
description Post‐translational modifications (PTMs) have emerged as key modulators of protein phase separation and have been linked to protein aggregation in neurodegenerative disorders. The major aggregating protein in amyotrophic lateral sclerosis and frontotemporal dementia, the RNA‐binding protein TAR DNA‐binding protein (TDP‐43), is hyperphosphorylated in disease on several C‐terminal serine residues, a process generally believed to promote TDP‐43 aggregation. Here, we however find that Casein kinase 1δ‐mediated TDP‐43 hyperphosphorylation or C‐terminal phosphomimetic mutations reduce TDP‐43 phase separation and aggregation, and instead render TDP‐43 condensates more liquid‐like and dynamic. Multi‐scale molecular dynamics simulations reveal reduced homotypic interactions of TDP‐43 low‐complexity domains through enhanced solvation of phosphomimetic residues. Cellular experiments show that phosphomimetic substitutions do not affect nuclear import or RNA regulatory functions of TDP‐43, but suppress accumulation of TDP‐43 in membrane‐less organelles and promote its solubility in neurons. We speculate that TDP‐43 hyperphosphorylation may be a protective cellular response to counteract TDP‐43 aggregation.
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spelling pubmed-90163522022-04-28 Disease‐linked TDP‐43 hyperphosphorylation suppresses TDP‐43 condensation and aggregation Gruijs da Silva, Lara A Simonetti, Francesca Hutten, Saskia Riemenschneider, Henrick Sternburg, Erin L Pietrek, Lisa M Gebel, Jakob Dötsch, Volker Edbauer, Dieter Hummer, Gerhard Stelzl, Lukas S Dormann, Dorothee EMBO J Articles Post‐translational modifications (PTMs) have emerged as key modulators of protein phase separation and have been linked to protein aggregation in neurodegenerative disorders. The major aggregating protein in amyotrophic lateral sclerosis and frontotemporal dementia, the RNA‐binding protein TAR DNA‐binding protein (TDP‐43), is hyperphosphorylated in disease on several C‐terminal serine residues, a process generally believed to promote TDP‐43 aggregation. Here, we however find that Casein kinase 1δ‐mediated TDP‐43 hyperphosphorylation or C‐terminal phosphomimetic mutations reduce TDP‐43 phase separation and aggregation, and instead render TDP‐43 condensates more liquid‐like and dynamic. Multi‐scale molecular dynamics simulations reveal reduced homotypic interactions of TDP‐43 low‐complexity domains through enhanced solvation of phosphomimetic residues. Cellular experiments show that phosphomimetic substitutions do not affect nuclear import or RNA regulatory functions of TDP‐43, but suppress accumulation of TDP‐43 in membrane‐less organelles and promote its solubility in neurons. We speculate that TDP‐43 hyperphosphorylation may be a protective cellular response to counteract TDP‐43 aggregation. John Wiley and Sons Inc. 2022-02-03 /pmc/articles/PMC9016352/ /pubmed/35112738 http://dx.doi.org/10.15252/embj.2021108443 Text en © 2022 The Authors. Published under the terms of the CC BY 4.0 license https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Gruijs da Silva, Lara A
Simonetti, Francesca
Hutten, Saskia
Riemenschneider, Henrick
Sternburg, Erin L
Pietrek, Lisa M
Gebel, Jakob
Dötsch, Volker
Edbauer, Dieter
Hummer, Gerhard
Stelzl, Lukas S
Dormann, Dorothee
Disease‐linked TDP‐43 hyperphosphorylation suppresses TDP‐43 condensation and aggregation
title Disease‐linked TDP‐43 hyperphosphorylation suppresses TDP‐43 condensation and aggregation
title_full Disease‐linked TDP‐43 hyperphosphorylation suppresses TDP‐43 condensation and aggregation
title_fullStr Disease‐linked TDP‐43 hyperphosphorylation suppresses TDP‐43 condensation and aggregation
title_full_unstemmed Disease‐linked TDP‐43 hyperphosphorylation suppresses TDP‐43 condensation and aggregation
title_short Disease‐linked TDP‐43 hyperphosphorylation suppresses TDP‐43 condensation and aggregation
title_sort disease‐linked tdp‐43 hyperphosphorylation suppresses tdp‐43 condensation and aggregation
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9016352/
https://www.ncbi.nlm.nih.gov/pubmed/35112738
http://dx.doi.org/10.15252/embj.2021108443
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