title: Stepwise acquirement of hallmark neuropathology in FUS-ALS iPSC models depends on mutation type and neuronal aging.
abstract: Autosomal-dominant mutations within the gene FUS (fused in sarcoma) are responsible for 5% of familial cases of amyotrophic lateral sclerosis (ALS). The FUS protein is physiologically mainly located in the nucleus, while cytoplasmic FUS aggregates are pathological hallmarks of FUS-ALS. Data from non-neuronal cell models and/or models using heterologous expression of FUS mutants suggest cytoplasmic FUS translocation as a pivotal initial event which leads to neurodegeneration depending on a second hit. Here we present the first human model of FUS-ALS using patient-derived neurons carrying endogenous FUS mutations leading to a benign (R521C) or a more severe clinical phenotype (frameshift mutation R495QfsX527). We thereby showed that the severity of the underlying FUS mutation determines the amount of cytoplasmic FUS accumulation and cellular vulnerability to exogenous stress. Cytoplasmic FUS inclusions formed spontaneously depending on both, severity of FUS mutation and neuronal aging. These aggregates showed typical characteristics of FUS-ALS including methylated FUS. Finally, neurodegeneration was not specific to layer V cortical neurons perfectly in line with the current model of disease spreading in ALS. Our study highlights the value and usefulness of patient-derived cell models in FUS-ALS.
authors.affiliation: Division for Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Japtok
authors.affiliation: Division for Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Xenia
authors.initials: X
authors.lastname: Lojewski
authors.affiliation: Division for Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Naumann
authors.affiliation: Institute of Neuroanatomy, Eberhard Karls University of Tübingen, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Klingenstein
authors.affiliation: Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Reinhardt
authors.affiliation: Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Jared
authors.initials: J
authors.lastname: Sterneckert
authors.affiliation: Institute of Anatomy and Cell Biology, University of Ulm, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Putz
authors.affiliation: Institute of Anatomy and Cell Biology, University of Ulm, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Demestre
authors.affiliation: Institute of Anatomy and Cell Biology, University of Ulm, Germany.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Boeckers
authors.affiliation: Department of Neurology, University Ulm, Germany.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.affiliation: Institute of Neuroanatomy, Eberhard Karls University of Tübingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Liebau
authors.affiliation: Division for Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany; German Center for Neurodegenerative Diseases (DZNE), 01307 Dresden, Germany; Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Storch
authors.affiliation: Division for Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany; German Center for Neurodegenerative Diseases (DZNE), 01307 Dresden, Germany. Electronic address: Andreas.Hermann@uniklinikum-dresden.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hermann
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D002540:Cerebral Cortex / Q000473:pathology / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology / Q000502:physiology; D057026:Induced Pluripotent Stem Cells / Q000473:pathology* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000473:pathology / Q000502:physiology; D009154:Mutation; D009474:Neurons / Q000473:pathology* / Q000502:physiology; D010641:Phenotype; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology
chemical_list: C000599550:FUS protein, human; D034702:RNA-Binding Protein FUS
keywords: Aggregate prone disease; Amyotrophic lateral sclerosis; Cortical neurodegeneration; Disease spreading; FUS-FTLD; Frontotemporal dementia; Fused in sarcoma; Human cell models; Motor neuron disease; RNA granules; Stress granules; Translated in sarcoma; iPSC