title: Nuclear transport dysfunction: a common theme in amyotrophic lateral sclerosis and frontotemporal dementia.
abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlapping genetic factors and pathology. On the cellular level, a majority of ALS and FTD cases are characterized by nuclear clearance and cytoplasmic aggregation of otherwise nuclear proteins, TAR DNA-binding protein 43 (TDP-43), or fused in sarcoma. Recent studies investigating cellular pathways perturbed by genetic risk factors for ALS/FTD converge on nucleocytoplasmic transport dysfunction as a mechanism leading to disease pathophysiology. We propose that mutations in FUS and hexanucleotide expansions in C9orf72 and aging all converge on the impairment of nucleocytoplasmic transport, which results in the hallmark pathological feature of ALS/FTD - cytoplasmic aggregation of TDP-43 or FUS.
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Jovičić
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Paul
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D034702:RNA-Binding Protein FUS / Q000235:genetics; D057177:TDP-43 Proteinopathies / Q000235:genetics / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; C000599550:FUS protein, human; D034702:RNA-Binding Protein FUS; C000598624:TARDBP protein, human
keywords: ALS; C9orf72; FTD; FUS; TDP-43; nucleocytoplasmic transport