Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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Gewählte Publikation:

SHR Neuro Krebs Kardio Lipid

Hofweber, M; Hutten, S; Bourgeois, B; Spreitzer, E; Niedner-Boblenz, A; Schifferer, M; Ruepp, MD; Simons, M; Niessing, D; Madl, T; Dormann, D.
Phase Separation of FUS Is Suppressed by Its Nuclear Import Receptor and Arginine Methylation.
Cell. 2018; 173(3):706-719
Web of Science PubMed FullText FullText_MUG

 

Autor/innen der Med Uni Graz:
Bourgeois Benjamin Michel Rene
Madl Tobias
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Abstract:
Cytoplasmic FUS aggregates are a pathological hallmark in a subset of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). A key step that is disrupted in these patients is nuclear import of FUS mediated by the import receptor Transportin/Karyopherin-β2. In ALS-FUS patients, this is caused by mutations in the nuclear localization signal (NLS) of FUS that weaken Transportin binding. In FTD-FUS patients, Transportin is aggregated, and post-translational arginine methylation, which regulates the FUS-Transportin interaction, is lost. Here, we show that Transportin and arginine methylation have a crucial function beyond nuclear import-namely to suppress RGG/RG-driven phase separation and stress granule association of FUS. ALS-associated FUS-NLS mutations weaken the chaperone activity of Transportin and loss of FUS arginine methylation, as seen in FTD-FUS, promote phase separation, and stress granule partitioning of FUS. Our findings reveal two regulatory mechanisms of liquid-phase homeostasis that are disrupted in FUS-associated neurodegeneration. Copyright © 2018 Elsevier Inc. All rights reserved.

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