Authors:	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
Title:	Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation
Online publication date:	3-Feb-2023
Year of first publication:	2022
Language:	english
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.
DDC:	570 Biowissenschaften 570 Life sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 10 Biologie
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-8712
Version:	Published version
Publication type:	Zeitschriftenaufsatz
Document type specification:	Scientific article
License:	CC BY
Information on rights of use:	https://creativecommons.org/licenses/by/4.0/
Journal:	The EMBO journal 41 8
Pages or article number:	108443
Publisher:	Wiley
Publisher place:	Hoboken, NJ
Issue date:	2022
ISSN:	1460-2075
Publisher DOI:	10.15252/embj.2021108443
Appears in collections:	DFG-491381577-H