dc.contributor.author | Nishimura, AL | en_US |
dc.contributor.author | Shum, C | en_US |
dc.contributor.author | Scotter, EL | en_US |
dc.contributor.author | Abdelgany, A | en_US |
dc.contributor.author | Sardone, V | en_US |
dc.contributor.author | Wright, J | en_US |
dc.contributor.author | Lee, Y-B | en_US |
dc.contributor.author | Chen, H-J | en_US |
dc.contributor.author | Bilican, B | en_US |
dc.contributor.author | Carrasco, M | en_US |
dc.contributor.author | Maniatis, T | en_US |
dc.contributor.author | Chandran, S | en_US |
dc.contributor.author | Rogelj, B | en_US |
dc.contributor.author | Gallo, J-M | en_US |
dc.contributor.author | Shaw, CE | en_US |
dc.date.accessioned | 2024-01-02T15:34:10Z | |
dc.date.available | 2014-02-10 | en_US |
dc.date.issued | 2014 | en_US |
dc.identifier.uri | https://qmro.qmul.ac.uk/xmlui/handle/123456789/93261 | |
dc.description.abstract | TDP-43 is found in cytoplasmic inclusions in 95% of amyotrophic lateral sclerosis (ALS) and 60% of frontotemporal lobar degeneration (FTLD). Approximately 4% of familial ALS is caused by mutations in TDP-43. The majority of these mutations are found in the glycine-rich domain, including the variant M337V, which is one of the most common mutations in TDP-43. In order to investigate the use of allele-specific RNA interference (RNAi) as a potential therapeutic tool, we designed and screened a set of siRNAs that specifically target TDP-43(M337V) mutation. Two siRNA specifically silenced the M337V mutation in HEK293T cells transfected with GFP-TDP-43(wt) or GFP-TDP-43(M337V) or TDP-43 C-terminal fragments counterparts. C-terminal TDP-43 transfected cells show an increase of cytosolic inclusions, which are decreased after allele-specific siRNA in M337V cells. We then investigated the effects of one of these allele-specific siRNAs in induced pluripotent stem cells (iPSCs) derived from an ALS patient carrying the M337V mutation. These lines showed a two-fold increase in cytosolic TDP-43 compared to the control. Following transfection with the allele-specific siRNA, cytosolic TDP-43 was reduced by 30% compared to cells transfected with a scrambled siRNA. We conclude that RNA interference can be used to selectively target the TDP-43(M337V) allele in mammalian and patient cells, thus demonstrating the potential for using RNA interference as a therapeutic tool for ALS. | en_US |
dc.format.extent | e91269 - ? | en_US |
dc.language | eng | en_US |
dc.relation.ispartof | PLoS One | en_US |
dc.rights | Attribution 3.0 United States | * |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/us/ | * |
dc.subject | Alleles | en_US |
dc.subject | Amino Acid Substitution | en_US |
dc.subject | Amyotrophic Lateral Sclerosis | en_US |
dc.subject | Base Sequence | en_US |
dc.subject | DNA-Binding Proteins | en_US |
dc.subject | Gene Knockdown Techniques | en_US |
dc.subject | HEK293 Cells | en_US |
dc.subject | Humans | en_US |
dc.subject | Inclusion Bodies | en_US |
dc.subject | Induced Pluripotent Stem Cells | en_US |
dc.subject | Molecular Sequence Data | en_US |
dc.subject | Mutation | en_US |
dc.subject | Neural Stem Cells | en_US |
dc.subject | RNA, Messenger | en_US |
dc.subject | RNA, Small Interfering | en_US |
dc.title | Allele-specific knockdown of ALS-associated mutant TDP-43 in neural stem cells derived from induced pluripotent stem cells. | en_US |
dc.type | Article | |
dc.identifier.doi | 10.1371/journal.pone.0091269 | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/24651281 | en_US |
pubs.issue | 3 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published online | en_US |
pubs.volume | 9 | en_US |
dcterms.dateAccepted | 2014-02-10 | en_US |
rioxxterms.funder | Default funder | en_US |
rioxxterms.identifier.project | Default project | en_US |