Wobst, HJ;
Wesolowski, SS;
Chadchankar, J;
Delsing, L;
Jacobsen, S;
Mukherjee, J;
Deeb, TZ;
... Moss, SJ; + view all
(2017)
Cytoplasmic Relocalization of TAR DNA-Binding Protein 43 Is Not Sufficient to Reproduce Cellular Pathologies Associated with ALS In vitro.
Frontiers in Molecular Neuroscience
, 10
, Article 46. 10.3389/fnmol.2017.00046.
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Abstract
Mutations in the gene TARDBP, 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.
| Type: | Article |
|---|---|
| Title: | Cytoplasmic Relocalization of TAR DNA-Binding Protein 43 Is Not Sufficient to Reproduce Cellular Pathologies Associated with ALS In vitro |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3389/fnmol.2017.00046 |
| Publisher version: | https://doi.org/10.3389/fnmol.2017.00046 |
| Language: | English |
| Additional information: | Copyright © 2017 Wobst, Wesolowski, Chadchankar, Delsing, Jacobsen, Mukherjee, Deeb, Dunlop, Brandon and Moss. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| Keywords: | amyotrophic lateral sclerosis (ALS), TAR DNA-binding protein 43 (TDP-43), neurodegenerative diseases, frontotemporal dementia, mutation, protein misfolding disease |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10080431 |
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