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Disease‐linked TDP‐43 hyperphosphorylation suppresses TDP‐43 condensation and aggregation

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Gruijs da Silva, Lara A, Simonetti, Francesca, Hutten, Saskia, Riemenschneider, Henrick, Sternburg, Erin L, Pietrek, Lisa M, Gebel, Jakob, Dötsch, Volker +4 more·2022·The EMBO Journal
DOI 10.15252/embj.2021108443PMC PMC9016352

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Abstract

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.

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Authors
Gruijs da Silva, L. A., Simonetti, F., Hutten, S., Riemenschneider, H., Sternburg, E. L., Pietrek, L. M., Gebel, J., Dötsch, V., Edbauer, D., Hummer, G., Stelzl, L. S., & Dormann, D.
Affiliations
  • Johannes Gutenberg University Mainz (DE)
  • German Center for Neurodegenerative Diseases (DE)
  • Max Planck Institute of Biophysics (DE)
  • Goethe University Frankfurt (DE)
Corresponding author
Dormann, Dorothee
ORCID
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2022-02-03
Volume
41
Issue
8
Pages
e108443-e108443
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
DOI
10.15252/embj.2021108443
PMC
PMC9016352
OpenAlex
W4210544859
Cited by
192
References
1
Citations by year
2026: 37 · 2025: 53 · 2024: 39 · 2023: 31 · 2022: 30 · 2021: 2
FWCI
20.22
Type
journal article
Language
en
Open access
Licence
Locations
  • The EMBO Journal (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Gutenberg Open Science (submittedVersion, cc-by-nd)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
  • mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
  • DZNE Pub (submittedVersion, other-oa)
  • Gutenberg Open Science (cc-by)
Funders
  • NOMIS Stiftung
  • Max‐Planck‐Gesellschaft
  • Paul Ehrlich and Ludwig Darmstädter Award for Young Researchers 2019
  • Deutsche Forschungsgemeinschaft (402723784, 390857198, CRC 902, DO1804/1‐1, DO1804/1‐2, DO1804/5‐1)
  • Forschungsinitiative des Landes Rheinland‐Pfalz
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Keywords
TDP-43, hyperphosphorylation, CK1δ, phase separation, protein condensates, protein aggregation, low-complexity domains, phosphomimetic mutations, neurodegenerative diseases, amyotrophic lateral sclerosis, frontotemporal dementia, biomolecular condensates, post-translational modification
MeSH terms
Amyotrophic Lateral Sclerosis, DNA-Binding Proteins, Humans, RNA-Binding Proteins, Frontotemporal Dementia, Protein Aggregates

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