Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation
da Silva Lg,Simonetti F,Simonetti F,Hutten S,Riemenschneider H,Sternburg El,Lisa M. Pietrek,Jakob Gebel,Dötsch,Dieter Edbauer,Gerhard Hummer,Gerhard Hummer,Lukas S. Stelzl,Dorothee Dormann,Dorothee Dormann +14 more
TLDR
This article showed that TDP-43 hyperphosphorylation by Casein kinase 1δ or C-terminal phosphomimetic mutations surprisingly reduced phase separation and aggregation, and rendered the protein more liquid-like and dynamic.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 (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.read more
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Post-translational modifications on RNA-binding proteins: accelerators, brakes, or passengers in neurodegeneration?
TL;DR: In this article, post-translational modifications (PTMs) have been used to regulate RNA-binding proteins (RBPs), which allow the cell to quickly and efficiently respond to cellular and environmental stimuli.
Journal ArticleDOI
TDP-43 pathology: From noxious assembly to therapeutic removal
TL;DR: In this article , the authors explore how the pathogenic changes to TDP-43, including mislocalisation, misfolding, aberrant liquid-liquid phase separation, stress granule assembly, oligomerization, and post-translational modification, drive diseaseassociated aggregation in TDP43 proteinopathies.
Journal ArticleDOI
Heterotypic electrostatic interactions control complex phase separation of tau and prion into multiphasic condensates and co-aggregates
TL;DR: These studies unveil an intriguing orchestra of molecular events associated with the formation of heterotypic condensates comprising ephemeral, domain-specific, short-range electrostatic nanoclusters and provide mechanistic underpinnings of overlapping neuropathology involving tau and PrP and highlight a broader role of complex phase transitions in physiology and disease.
Posted ContentDOI
Opposing roles of p38α-mediated phosphorylation and arginine methylation in driving TDP-43 proteinopathy
Mari Aikio,Heike J. Wobst,Hana M. Odeh,Bo Lim Lee,Bradley Class,Thomas A. Ollerhead,Korrie L. Mack,Alice Flynn Ford,Edward M. Barbieri,Ryan R. Cupo,Lauren E. Drake,Nicholas A. Castello,Ashmita Baral,John Dunlop,Aaron D. Gitler,Ashkan Javaherian,Steven Finkbeiner,Steven Finkbeiner,Dean G. Brown,Stephen J. Moss,Nicholas J. Brandon,Nicholas J. Brandon,James Shorter +22 more
TL;DR: In this article, the authors demonstrate that inhibition of p38α MAPK reduces pathological TDP-43 phosphorylation, aggregation, cytoplasmic mislocalization, and neurotoxicity.
Journal ArticleDOI
Biophysical characterization of full‐length TAR DNA‐binding protein (TDP‐43) phase separation
TL;DR: In this article , a phase separation of full-length TAR DNA-binding protein 43 (TDP•43) was performed using a solution-jump method and monitored with an array of biophysical techniques, including confocal fluorescence, bright field and stimulated emission depletion microscopy.
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