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

Gruijs da Silva, L. A., Simonetti, F., Hutten, S., Riemenschneider, H., Sternburg, E. L., Pietrek, L. M., et al. (2022). Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation. EMBO Journal, 41(3): e108443. doi:10.15252/embj.2021108443.

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Gruijs da Silva, Lara A.1, 2, Autor
Simonetti, Francesca1, 2, 3, Autor
Hutten, Saskia1, Autor
Riemenschneider, Henrick3, Autor
Sternburg, Erin L.1, Autor
Pietrek, Lisa M.4, Autor           
Gebel, Jakob5, Autor
Dötsch, Volker5, Autor
Edbauer, Dieter2, 3, 6, Autor
Hummer, Gerhard4, 7, Autor                 
Stelzl, Lukas S.1, 4, 8, 9, Autor                 
Dormann, Dorothee1, 6, 9, Autor
Affiliations:
1Biocenter, Institute of Molecular Physiology, Johannes Gutenberg-Universität (JGU), Mainz, Germany , ou_persistent22              
2Graduate School of Systemic Neurosciences (GSN), Planegg-Martinsried, Germany, ou_persistent22              
3German Center for Neurodegenerative Diseases (DZNE), Munich, Germany, ou_persistent22              
4Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society, ou_2068292              
5Institute for Biophysical Chemistry, Goethe-Universität, Frankfurt am Main, Germany, ou_persistent22              
6Munich Cluster for Systems Neurology (SyNergy) Munich, Munich, Germany, ou_persistent22              
7Institute for Biophysics, Goethe-Universität, Frankfurt am Main, Germany, ou_persistent22              
8KOMET1, Institute of Physics, Johannes Gutenberg-Universität (JGU), Mainz, Germany, ou_persistent22              
9Institute of Molecular Biology (IMB), Mainz, Germany, ou_persistent22              

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Schlagwörter: neurodegeneration, phase separation, phosphorylation, RNA-binding protein, TDP-43
 Zusammenfassung: 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.

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Sprache(n): eng - English
 Datum: 2021-12-232021-04-152022-01-042022-02-03
 Publikationsstatus: Online veröffentlicht
 Seiten: 23
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: DOI: 10.15252/embj.2021108443
BibTex Citekey: gruijs_da_silva_disease-linked_2022
 Art des Abschluß: -

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Titel: EMBO Journal
  Andere : EMBO J.
Genre der Quelle: Zeitschrift
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Affiliations:
Ort, Verlag, Ausgabe: Nature Publishing Group
Seiten: - Band / Heft: 41 (3) Artikelnummer: e108443 Start- / Endseite: - Identifikator: ISSN: 0261-4189
CoNE: https://pure.mpg.de/cone/journals/resource/954925497061