Journal Article

DZNE-2022-00269

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation.

Gruijs da Silva, L. A.Extern* ; Simonetti, F.DZNE* ; Hutten, S. ; Riemenschneider, H.DZNE* ; Sternburg, E. L. ; Pietrek, L. M. ; Gebel, J. ; Dötsch, V. ; Edbauer, D.DZNE* ; Hummer, G. ; Stelzl, L. S. ; Dormann, D.Extern*

2022
Wiley Hoboken, NJ [u.a.]

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Please use a persistent id in citations: doi:10.15252/embj.2021108443

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 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.

Keyword(s): Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; DNA-Binding Proteins: metabolism (MeSH) ; Frontotemporal Dementia (MeSH) ; Humans (MeSH) ; Protein Aggregates (MeSH) ; RNA-Binding Proteins: genetics (MeSH) ; RNA-Binding Proteins: metabolism (MeSH) ; RNA-binding protein ; TDP-43 ; neurodegeneration ; phase separation ; phosphorylation

Note: (CC BY)

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Contributing Institute(s):

1. Ext Ludwig-Maximilians-University (Ext LMU)
2. Cell Biology of Neurodegeneration (AG Edbauer)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2022

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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