Gutenberg Open Science: Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation

Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-8712

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DC Field	Value	Language
dc.contributor.author	Gruijs da Silva, Lara A.	-
dc.contributor.author	Simonetti, Francesca	-
dc.contributor.author	Hutten, Saskia	-
dc.contributor.author	Riemenschneider, Henrick	-
dc.contributor.author	Sternburg, Erin L.	-
dc.contributor.author	Pietrek, Lisa M.	-
dc.contributor.author	Gebel, Jakob	-
dc.contributor.author	Dötsch, Volker	-
dc.contributor.author	Edbauer, Dieter	-
dc.contributor.author	Hummer, Gerhard	-
dc.contributor.author	Stelzl, Lukas S.	-
dc.contributor.author	Dormann, Dorothee	-
dc.date.accessioned	2023-02-03T12:05:32Z	-
dc.date.available	2023-02-03T12:05:32Z	-
dc.date.issued	2022	-
dc.identifier.uri	https://openscience.ub.uni-mainz.de/handle/20.500.12030/8728	-
dc.description.abstract	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 Cterminal 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.	en_GB
dc.description.sponsorship	Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 491381577	de
dc.language.iso	eng	de
dc.rights	CC BY	*
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/	*
dc.subject.ddc	570 Biowissenschaften	de_DE
dc.subject.ddc	570 Life sciences	en_GB
dc.title	Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation	en_GB
dc.type	Zeitschriftenaufsatz	de
dc.identifier.doi	http://doi.org/10.25358/openscience-8712	-
jgu.type.contenttype	Scientific article	de
jgu.type.dinitype	article	en_GB
jgu.type.version	Published version	de
jgu.type.resource	Text	de
jgu.organisation.department	FB 10 Biologie	de
jgu.organisation.number	7970	-
jgu.organisation.name	Johannes Gutenberg-Universität Mainz	-
jgu.rights.accessrights	openAccess	-
jgu.journal.title	The EMBO journal	de
jgu.journal.volume	41	de
jgu.journal.issue	8	de
jgu.pages.alternative	108443	de
jgu.publisher.year	2022	-
jgu.publisher.name	Wiley	de
jgu.publisher.place	Hoboken, NJ	de
jgu.publisher.issn	1460-2075	de
jgu.organisation.place	Mainz	-
jgu.subject.ddccode	570	de
jgu.publisher.doi	10.15252/embj.2021108443	de
jgu.organisation.ror	https://ror.org/023b0x485	-
jgu.subject.dfg	Naturwissenschaften	de
Appears in collections:	DFG-491381577-H

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diseaselinked_tdp43_hyperphos-20230130175249618.pdf	Hauptdatei	6.73 MB	Adobe PDF	View/Open
diseaselinked_tdp43_hyperphos-20230130175304603.pdf	Appendix	2.62 MB	Adobe PDF	View/Open
diseaselinked_tdp43_hyperphos-20230130175316572.pdf	Expanded view figures	4.1 MB	Adobe PDF	View/Open

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