title: ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function.
abstract: The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins.
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Medical Biophysics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 3H2, Canada.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Murakami
authors.affiliation: Cambridge Institute for Medical Research, Cambridge National Institute for Health Research - Biomedical Research Unit in Dementia, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Seema
authors.initials: S
authors.lastname: Qamar
authors.affiliation: Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
authors.forename: Julie Qiaojin
authors.initials: JQ
authors.lastname: Lin
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK.
authors.forename: Gabriele S Kaminski
authors.initials: GS
authors.lastname: Schierle
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK.
authors.forename: Eric
authors.initials: E
authors.lastname: Rees
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Medical Biophysics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 3H2, Canada.
authors.forename: Akinori
authors.initials: A
authors.lastname: Miyashita
authors.affiliation: Cambridge Institute for Medical Research, Cambridge National Institute for Health Research - Biomedical Research Unit in Dementia, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Costa
authors.affiliation: Cambridge Institute for Medical Research, Cambridge National Institute for Health Research - Biomedical Research Unit in Dementia, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Dodd
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK.
authors.forename: Fiona T S
authors.initials: FT
authors.lastname: Chan
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK.
authors.forename: Claire H
authors.initials: CH
authors.lastname: Michel
authors.affiliation: Cambridge Institute for Medical Research, Cambridge National Institute for Health Research - Biomedical Research Unit in Dementia, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Kronenberg-Versteeg
authors.affiliation: Cambridge Institute for Medical Research, Cambridge National Institute for Health Research - Biomedical Research Unit in Dementia, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Medical Biophysics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 3H2, Canada.
authors.forename: Seung-Pil
authors.initials: SP
authors.lastname: Yang
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Medical Biophysics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 3H2, Canada.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Wakutani
authors.affiliation: Cambridge Institute for Medical Research, Cambridge National Institute for Health Research - Biomedical Research Unit in Dementia, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: William
authors.initials: W
authors.lastname: Meadows
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Medical Biophysics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 3H2, Canada.
authors.forename: Rodylyn Rose
authors.initials: RR
authors.lastname: Ferry
authors.affiliation: Cambridge Institute for Medical Research, Cambridge National Institute for Health Research - Biomedical Research Unit in Dementia, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Liang
authors.initials: L
authors.lastname: Dong
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK; Centre for Genomic Regulation and University Pompeu Fabra, Dr. Aiguader St. 88, and Universitat Pompeu Fabra, 08003, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 23 Passeig Lluís Companys, 08010 Barcelona, Spain.
authors.forename: Gian Gaetano
authors.initials: GG
authors.lastname: Tartaglia
authors.affiliation: Cambridge Systems Biology Center & Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Favrin
authors.affiliation: Department of Research, Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Wen-Lang
authors.initials: WL
authors.lastname: Lin
authors.affiliation: Department of Research, Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhen
authors.affiliation: Department of Clinical Biochemistry, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Medical Biophysics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 3H2, Canada.
authors.forename: Gerold
authors.initials: G
authors.lastname: Schmitt-Ulms
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Medical Biophysics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 3H2, Canada.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Fraser
authors.affiliation: Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Shneider
authors.affiliation: Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
authors.forename: Christine
authors.initials: C
authors.lastname: Holt
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK.
authors.forename: Clemens F
authors.initials: CF
authors.lastname: Kaminski
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Medical Biophysics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 3H2, Canada; Cambridge Institute for Medical Research, Cambridge National Institute for Health Research - Biomedical Research Unit in Dementia, University of Cambridge, Cambridge CB2 0XY, UK. Electronic address: phs22@cam.ac.uk.
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D003594:Cytoplasmic Granules / Q000378:metabolism; D004195:Disease Models, Animal; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics*; D020100:Hydrogels; D008136:Longevity; D009043:Motor Activity / Q000235:genetics*; D009154:Mutation; D044367:Phase Transition; D012333:RNA, Messenger / Q000378:metabolism*; D034702:RNA-Binding Protein FUS / Q000737:chemistry / Q000235:genetics*; D012261:Ribonucleoproteins / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D020100:Hydrogels; D012333:RNA, Messenger; D034702:RNA-Binding Protein FUS; D012261:Ribonucleoproteins