TY  - JOUR
AU  - Gruijs da Silva, Lara Aletta
AU  - Simonetti, Francesca
AU  - Hutten, Saskia
AU  - Riemenschneider, Henrick
AU  - Sternburg, Erin L
AU  - Pietrek, Lisa M
AU  - Gebel, Jakob
AU  - Dötsch, Volker
AU  - Edbauer, Dieter
AU  - Hummer, Gerhard
AU  - Stelzl, Lukas S
AU  - Dormann, Dorothee
TI  - Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation.
JO  - The EMBO journal
VL  - 41
IS  - 8
SN  - 1460-2075
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DZNE-2022-00269
SP  - e108443
PY  - 2022
N1  - (CC BY)
AB  - 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.
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - DNA-Binding Proteins: metabolism
KW  - Frontotemporal Dementia
KW  - Humans
KW  - Protein Aggregates
KW  - RNA-Binding Proteins: genetics
KW  - RNA-Binding Proteins: metabolism
KW  - RNA-binding protein (Other)
KW  - TDP-43 (Other)
KW  - neurodegeneration (Other)
KW  - phase separation (Other)
KW  - phosphorylation (Other)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC9016352
C6  - pmid:35112738
DO  - DOI:10.15252/embj.2021108443
UR  - https://pub.dzne.de/record/163509
ER  -