title: Nuclear trafficking in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.
abstract: Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are two ends of a phenotypic spectrum of disabling, relentlessly progressive and ultimately fatal diseases. A key characteristic of both conditions is the presence of TDP-43 (encoded by TARDBP) or FUS immunoreactive cytoplasmic inclusions in neuronal and glial cells. This cytoplasmic mislocalization of otherwise predominantly nuclear RNA binding proteins implies a perturbation of the nucleocytoplasmic shuttling as a possible event in the pathogenesis. Compromised nucleocytoplasmic shuttling has recently also been associated with a hexanucleotide repeat expansion mutation in C9orf72, which is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and leads to accumulation of cytoplasmic TDP-43 inclusions. Mutation in C9orf72 may disrupt nucleocytoplasmic shuttling on the level of C9ORF72 protein, the transcribed hexanucleotide repeat RNA, and/or dipeptide repeat proteins translated form the hexanucleotide repeat RNA. These defects of nucleocytoplasmic shuttling may therefore, constitute the common ground of the underlying disease mechanisms in different molecular subtypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration.
authors: 1 Department of Biotechnology, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia.
authors: Sonja
authors: S
authors: Prpar Mihevc
authors: 1 Department of Biotechnology, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia.
authors: Simona
authors: S
authors: Darovic
authors: 1 Department of Biotechnology, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia.
authors: Anja
authors: A
authors: Kovanda
authors: 1 Department of Biotechnology, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia.
authors: Ana
authors: A
authors: Bajc Česnik
authors: 2 Faculty of Chemistry and Chemical Technology, Večna pot 113, University of Ljubljana, SI-1000 Ljubljana, Slovenia.
authors: Vera
authors: V
authors: Župunski
authors: 1 Department of Biotechnology, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia boris.rogelj@ijs.si.|2 Faculty of Chemistry and Chemical Technology, Večna pot 113, University of Ljubljana, SI-1000 Ljubljana, Slovenia.|3 Biomedical Research Institute BRIS, Puhova 10, SI-1000 Ljubljana, Slovenia.
authors: Boris
authors: B
authors: Rogelj
mesh_terms: D021581:Active Transport, Cell Nucleus; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000073885:C9orf72 Protein; D002467:Cell Nucleus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism*; D006801:Humans; D011506:Proteins / Q000378:metabolism*; D034702:RNA-Binding Protein FUS / Q000378:metabolism*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; C000599550:FUS protein, human; D011506:Proteins; D034702:RNA-Binding Protein FUS; C000598624:TARDBP protein, human
keywords: C9ORF72; FUS; TDP-43; amyotrophic lateral sclerosis; frontotemporal lobar degeneration; nucleocytoplasmic transport