RT Journal Article
SR Electronic
T1 Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.04.30.442163
DO 10.1101/2021.04.30.442163
A1 Lara Gruijs da Silva
A1 Francesca Simonetti
A1 Saskia Hutten
A1 Henrick Riemenschneider
A1 Erin L. Sternburg
A1 Lisa M. Pietrek
A1 Jakob Gebel
A1 Volker Dötsch
A1 Dieter Edbauer
A1 Gerhard Hummer
A1 Lukas S. Stelzl
A1 Dorothee Dormann
YR 2021
UL http://biorxiv.org/content/early/2021/04/30/2021.04.30.442163.abstract
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 (ALS) and frontotemporal dementia (FTD), the RNA-binding protein TDP-43, is hyperphosphorylated in disease on several C-terminal serine residues, which is generally believed to promote TDP-43 aggregation. Here, we show that hyperphosphorylation by Casein kinase 1δ or C-terminal phosphomimetic mutations surprisingly reduce TDP-43 phase separation and aggregation and render TDP-43 condensates more liquid-like and dynamic. Multi-scale 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 propose that TDP-43 hyperphosphorylation may be a protective cellular response to counteract TDP-43 aggregation.Competing Interest StatementThe authors have declared no competing interest.