title: TDP-43 and FUS: a nuclear affair.
abstract: Misfolded TAR DNA binding protein 43 (TDP-43) and Fused-In-Sarcoma (FUS) protein have recently been identified as pathological hallmarks of the neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) characterized by the presence of ubiquitin-positive inclusions (FTLD-U). Although TDP-43 and FUS are normally located predominantly in the nucleus, pathological TDP-43 and FUS inclusions are mostly found in the cytosol. Cytosolic deposition is paralleled by a striking nuclear depletion of either protein. Based on a number of recent findings, we postulate that defects in nuclear import are an important step towards TDP-43 and FUS dysfunction. Failure of nuclear transport can arise from mutations within a nuclear localization signal or from age-related decline of nuclear import mechanisms. We propose that nuclear import defects in combination with additional hits, for example cellular stress and genetic risk factors, may be a central underlying cause of ALS and FTLD-U pathology.
authors.affiliation: Adolf-Butenandt-Institute, Biochemistry, Ludwig-Maximilians-University and German Center for Neurodegenerative Diseases (DZNE) Munich, Schillerstr. 44, 80336 Munich, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Dormann
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000502:physiology; D034702:RNA-Binding Protein FUS / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D034702:RNA-Binding Protein FUS