title: Cytoplasmic Relocalization of TAR DNA-Binding Protein 43 Is Not Sufficient to Reproduce Cellular Pathologies Associated with ALSIn vitro.
abstract: Mutations in the geneTARDBP, which encodes TAR DNA-binding protein 43 (TDP-43), are a rare cause of familial forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While the majority of mutations are found in the C-terminal glycine-rich domain, an alanine to valine amino acid change at position 90 (A90V) in the bipartite nuclear localization signal (NLS) of TDP-43 has been described. This sequence variant has previously been shown to cause cytoplasmic mislocalization of TDP-43 and decrease protein solubility, leading to the formation of insoluble aggregates. Since the A90V mutation has been described both in patients as well as healthy controls, its pathogenic potential in ALS and FTD remains unclear. Here we compare properties of overexpressed A90V to the highly pathogenic M337V mutation. Though both mutations drive mislocalization of the protein to the cytoplasm to the same extent, M337V produces more significant damage in terms of protein solubility, levels of pathogenic phosphorylation, and formation of C-terminal truncated protein species. Furthermore, the M337V, but not the A90V mutant, leads to a downregulation of histone deacetylase 6 and Ras GTPase-activating protein-binding protein. We conclude that in the absence of another genetic or environmental 'hit' the A90V variant is not sufficient to cause the deleterious phenotypes associated with ALS and FTD, despite prominent cytoplasmic protein relocalization of TDP-43.
authors.affiliation: AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Department of Neuroscience, Tufts University School of Medicine, Boston MA, USA.
authors.forename: Heike J
authors.initials: HJ
authors.lastname: Wobst
authors.affiliation: IMED Biotech Unit, AstraZeneca Neuroscience IMED, AstraZeneca, Cambridge MA, USA.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Wesolowski
authors.affiliation: AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Department of Neuroscience, Tufts University School of Medicine, Boston MA, USA.
authors.forename: Jayashree
authors.initials: J
authors.lastname: Chadchankar
authors.affiliation: AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Department of Neuroscience, Tufts University School of Medicine, BostonMA, USA; IMED Biotech Unit, AstraZeneca Discovery ScienceMölndal, Sweden.
authors.forename: Louise
authors.initials: L
authors.lastname: Delsing
authors.affiliation: IMED Biotech Unit, AstraZeneca Neuroscience IMED, AstraZeneca, Cambridge MA, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Jacobsen
authors.affiliation: AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Department of Neuroscience, Tufts University School of Medicine, Boston MA, USA.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Mukherjee
authors.affiliation: AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Department of Neuroscience, Tufts University School of Medicine, Boston MA, USA.
authors.forename: Tarek Z
authors.initials: TZ
authors.lastname: Deeb
authors.affiliation: IMED Biotech Unit, AstraZeneca Neuroscience IMED, AstraZeneca, Cambridge MA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Dunlop
authors.affiliation: IMED Biotech Unit, AstraZeneca Neuroscience IMED, AstraZeneca, Cambridge MA, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Brandon
authors.affiliation: AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Department of Neuroscience, Tufts University School of Medicine, BostonMA, USA; Department of Neuroscience, Tufts University School of Medicine, BostonMA, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
keywords: TAR DNA-binding protein 43 (TDP-43); amyotrophic lateral sclerosis (ALS); frontotemporal dementia; mutation; neurodegenerative diseases; protein misfolding disease