title: TDP-43-mediated neurodegeneration: towards a loss-of-function hypothesis?
abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are clinically distinct fatal neurodegenerative disorders. Increasing molecular evidence indicates that both disorders are linked in a continuous spectrum (ALS-FTD spectrum). Neuronal cytoplasmic inclusions consisting of the nuclear TAR DNA-binding protein 43 (TDP-43) are found in the large majority of patients in the ALS-FTD spectrum and dominant mutations in the TDP-43 gene cause ALS. A major unresolved question is whether TDP-43-mediated neuronal loss is caused by toxic gain of function of cytoplasmic aggregates, or by a loss of its normal function in the nucleus. Here we argue that based on recent genetic studies in worms, flies, fish, and rodents, loss of function of TDP-43, rather than toxic aggregates, is the key factor in TDP-43-related proteinopathies.
authors.affiliation: Laboratory of Behavioral and Developmental Genetics, Center of Human Genetics, University of Leuven, B3000 Leuven, Belgium; VIB Center for the Biology of Disease, University of Leuven, B3000 Leuven, Belgium; Inserm U744, Institut Pasteur de Lille, Université de Lille Nord de France, 59019 Lille, France.
authors.forename: Lies
authors.initials: L
authors.lastname: Vanden Broeck
authors.affiliation: Laboratory of Behavioral and Developmental Genetics, Center of Human Genetics, University of Leuven, B3000 Leuven, Belgium; VIB Center for the Biology of Disease, University of Leuven, B3000 Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Callaerts
authors.affiliation: Inserm U744, Institut Pasteur de Lille, Université de Lille Nord de France, 59019 Lille, France. Electronic address: bart.dermaut@pasteur-lille.fr.
authors.forename: Bart
authors.initials: B
authors.lastname: Dermaut
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D016601:RNA-Binding Proteins
keywords: ALS; FTD; TDP-43; loss-of-function; neurodegeneration; proteinopathy