ALS/FTLD-Linked Mutations in FUS Glycine Residues Cause Accelerated Gelation and Reduced Interactions with Wild-Type FUS.

Tytuł:: ALS/FTLD-Linked Mutations in FUS Glycine Residues Cause Accelerated Gelation and Reduced Interactions with Wild-Type FUS.
Autorzy:: Rhine K; Program in Cell, Molecular, Developmental Biology, and Biophysics, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA; Department of Biology, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA.
Makurath MA; Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Department of Physics, Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Liu J; Department of Biology, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA; Medical Genetics and Ophthalmic Genomics Unit, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Skanchy S; Department of Biophysics, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA.
Lopez C; Department of Biology, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA.
Catalan KF; Program in Cell, Molecular, Developmental Biology, and Biophysics, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA; Department of Biology, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA.
Ma Y; Department of Biomedical Engineering, Johns Hopkins Medical Institute, 615 N Wolfe St, Baltimore, MD 21231, USA.
Fare CM; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Shorter J; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Ha T; Program in Cell, Molecular, Developmental Biology, and Biophysics, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA; Department of Physics, Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Department of Biophysics, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA; Department of Biomedical Engineering, Johns Hopkins Medical Institute, 615 N Wolfe St, Baltimore, MD 21231, USA; Howard Hughes Medical Institute, Baltimore, MD 21218, USA.
Chemla YR; Department of Physics, Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Myong S; Program in Cell, Molecular, Developmental Biology, and Biophysics, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA; Department of Physics, Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Department of Biophysics, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA. Electronic address: .
Źródło:: Molecular cell [Mol Cell] 2020 Nov 19; Vol. 80 (4), pp. 666-681.e8. Date of Electronic Publication: 2020 Nov 06.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
Język:: English
Imprint Name(s):: Publication: Cambridge Ma : Cell Press
Original Publication: Cambridge, Mass. : Cell Press, c1997-
MeSH Terms:: Mutation*
Amyotrophic Lateral Sclerosis/*pathology
Frontotemporal Dementia/*pathology
Glycine/*metabolism
Neuroblastoma/*pathology
RNA/*metabolism
RNA-Binding Protein FUS/*chemistry
RNA-Binding Protein FUS/*metabolism
Amyotrophic Lateral Sclerosis/genetics ; Frontotemporal Dementia/genetics ; Glycine/chemistry ; Glycine/genetics ; Humans ; Inclusion Bodies ; Neuroblastoma/genetics ; Neuroblastoma/metabolism ; Protein Conformation ; RNA/chemistry ; RNA/genetics ; RNA-Binding Protein FUS/genetics ; Tumor Cells, Cultured
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Grant Information:: F31 NS113439 United States NS NINDS NIH HHS; T32 GM007231 United States GM NIGMS NIH HHS; F31 NS111870 United States NS NINDS NIH HHS; RF1 NS113636 United States NS NINDS NIH HHS; R01 GM120353 United States GM NIGMS NIH HHS; R35 GM122569 United States GM NIGMS NIH HHS; R01 MH122569 United States MH NIMH NIH HHS; United States HHMI Howard Hughes Medical Institute; S10 OD021567 United States OD NIH HHS
Contributed Indexing:: Keywords: ALS/FTLD-linked mutation; FUS; LLPS; RNA; arrested dynamics; gelation; immiscibility; miscibility; nucleation; single molecule
Substance Nomenclature:: 0 (FUS protein, human)
0 (RNA-Binding Protein FUS)
63231-63-0 (RNA)
TE7660XO1C (Glycine)
SCR Disease Name:: Frontotemporal Dementia With Motor Neuron Disease
Entry Date(s):: Date Created: 20201107 Date Completed: 20201207 Latest Revision: 20240330
Update Code:: 20240330
PubMed Central ID:: PMC7688085
DOI:: 10.1016/j.molcel.2020.10.014
PMID:: 33159856
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The RNA-binding protein fused in sarcoma (FUS) can form pathogenic inclusions in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). Over 70 mutations in Fus are linked to ALS/FTLD. In patients, all Fus mutations are heterozygous, indicating that the mutant drives disease progression despite the presence of wild-type (WT) FUS. Here, we demonstrate that ALS/FTLD-linked FUS mutations in glycine (G) strikingly drive formation of droplets that do not readily interact with WT FUS, whereas arginine (R) mutants form mixed condensates with WT FUS. Remarkably, interactions between WT and G mutants are disfavored at the earliest stages of FUS nucleation. In contrast, R mutants physically interact with the WT FUS such that WT FUS recovers the mutant defects by reducing droplet size and increasing dynamic interactions with RNA. This result suggests disparate molecular mechanisms underlying ALS/FTLD pathogenesis and differing recovery potential depending on the type of mutation.
Competing Interests: Declaration of Interests The authors declare no competing interests.
(Copyright © 2020 Elsevier Inc. All rights reserved.)

Erratum in: Mol Cell. 2020 Dec 17;80(6):1139. (PMID: 33338404)
Comment in: Commun Biol. 2021 Jan 4;4(1):3. (PMID: 33398047)

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