title: Fused in sarcoma (FUS) protein lacking nuclear localization signal (NLS) and major RNA binding motifs triggers proteinopathy and severe motor phenotype in transgenic mice.
abstract: Dysfunction of two structurally and functionally related proteins, FUS and TAR DNA-binding protein of 43 kDa (TDP-43), implicated in crucial steps of cellular RNA metabolism can cause amyotrophic lateral sclerosis (ALS) and certain other neurodegenerative diseases. The proteins are intrinsically aggregate-prone and form non-amyloid inclusions in the affected nervous tissues, but the role of these proteinaceous aggregates in disease onset and progression is still uncertain. To address this question, we designed a variant of FUS, FUS 1-359, which is predominantly cytoplasmic, highly aggregate-prone, and lacks a region responsible for RNA recognition and binding. Expression of FUS 1-359 in neurons of transgenic mice, at a level lower than that of endogenous FUS, triggers FUSopathy associated with severe damage of motor neurons and their axons, neuroinflammatory reaction, and eventual loss of selective motor neuron populations. These pathological changes cause abrupt development of a severe motor phenotype at the age of 2.5-4.5 months and death of affected animals within several days of onset. The pattern of pathology in transgenic FUS 1-359 mice recapitulates several key features of human ALS with the dynamics of the disease progression compressed in line with shorter mouse lifespan. Our data indicate that neuronal FUS aggregation is sufficient to cause ALS-like phenotype in transgenic mice.
authors.affiliation: From the School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, Wales, United Kingdom,; the Institute of Physiologically Active Compounds, Russian Academy of Sciences, 1 Severniy proezd, Chernogolovka 142432, Moscow Region, Russian Federation.
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Shelkovnikova
authors.affiliation: From the School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, Wales, United Kingdom.
authors.forename: Owen M
authors.initials: OM
authors.lastname: Peters
authors.affiliation: the Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov Street, Moscow 119334, Russian Federation.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Deykin
authors.affiliation: From the School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, Wales, United Kingdom.
authors.forename: Natalie
authors.initials: N
authors.lastname: Connor-Robson
authors.affiliation: From the School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, Wales, United Kingdom.
authors.forename: Hannah
authors.initials: H
authors.lastname: Robinson
authors.affiliation: From the School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, Wales, United Kingdom,; the Institute of Physiologically Active Compounds, Russian Academy of Sciences, 1 Severniy proezd, Chernogolovka 142432, Moscow Region, Russian Federation.
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Ustyugov
authors.affiliation: the Institute of Physiologically Active Compounds, Russian Academy of Sciences, 1 Severniy proezd, Chernogolovka 142432, Moscow Region, Russian Federation.
authors.forename: Sergey O
authors.initials: SO
authors.lastname: Bachurin
authors.affiliation: the Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov Street, Moscow 119334, Russian Federation.
authors.forename: Tatyana G
authors.initials: TG
authors.lastname: Ermolkevich
authors.affiliation: the Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov Street, Moscow 119334, Russian Federation.
authors.forename: Igor L
authors.initials: IL
authors.lastname: Goldman
authors.affiliation: the Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov Street, Moscow 119334, Russian Federation.
authors.forename: Elena R
authors.initials: ER
authors.lastname: Sadchikova
authors.affiliation: the Pirogov Russian National Research Medical University, Ostrovitianov Str. 1, Moscow 117997, Russian Federation, and.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Kovrazhkina
authors.affiliation: the Pirogov Russian National Research Medical University, Ostrovitianov Str. 1, Moscow 117997, Russian Federation, and.
authors.forename: Veronica I
authors.initials: VI
authors.lastname: Skvortsova
authors.affiliation: the Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093.
authors.forename: Shuo-Chien
authors.initials: SC
authors.lastname: Ling
authors.affiliation: the Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Da Cruz
authors.affiliation: the Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093.
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Parone
authors.affiliation: From the School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, Wales, United Kingdom,; the Institute of Physiologically Active Compounds, Russian Academy of Sciences, 1 Severniy proezd, Chernogolovka 142432, Moscow Region, Russian Federation,. Electronic address: buchmanvl@cf.ac.uk.
authors.forename: Vladimir L
authors.initials: VL
authors.lastname: Buchman
authors.affiliation: From the School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, Wales, United Kingdom,; the Institute of Physiologically Active Compounds, Russian Academy of Sciences, 1 Severniy proezd, Chernogolovka 142432, Moscow Region, Russian Federation,. Electronic address: ninkinan@cf.ac.uk.
authors.forename: Natalia N
authors.initials: NN
authors.lastname: Ninkina
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D019913:Nuclear Localization Signals; D010641:Phenotype; D012313:RNA; D034702:RNA-Binding Protein FUS / Q000096:biosynthesis* / Q000235:genetics; D017384:Sequence Deletion
chemical_list: D019913:Nuclear Localization Signals; D034702:RNA-Binding Protein FUS; D012313:RNA
keywords: Amyotrophic Lateral Sclerosis (Lou Gehrig's Disease); Animal Models; Motor Neuron Disease; Neurodegeneration; Protein Aggregation; Proteinopathy; RNA Metabolism; RNA-binding Proteins; TDP-43; Transgenic Mouse