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Yeast genetic screen reveals novel therapeutic strategy for ALS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by a selective loss of motor neurons. There is no cure and few effective treatments. The RNA-binding protein TDP-43 contributes to the pathogenesis of ALS. TDP-43 is depleted from the nucleus and accumulates in cytoplasmic agg...

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Autores principales: Figley, Matthew D., Gitler, Aaron D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Landes Bioscience 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933050/
https://www.ncbi.nlm.nih.gov/pubmed/25002991
http://dx.doi.org/10.4161/rdis.24420
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author Figley, Matthew D.
Gitler, Aaron D.
author_facet Figley, Matthew D.
Gitler, Aaron D.
author_sort Figley, Matthew D.
collection PubMed
description Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by a selective loss of motor neurons. There is no cure and few effective treatments. The RNA-binding protein TDP-43 contributes to the pathogenesis of ALS. TDP-43 is depleted from the nucleus and accumulates in cytoplasmic aggregates in the degenerating neurons and glia of most ALS patients. Furthermore, mutations in the TDP-43 gene cause rare familial and sporadic forms of the disease. Thus, therapeutic strategies targeting TDP-43 may be efficacious. We have used the yeast model system to identify the mechanisms by which TDP-43 aggregation contributes to ALS and to identify approaches to protect cells from the toxic effects of TDP-43 aggregation. Using an unbiased yeast genetic screen we discovered Dbr1 as a potent suppressor of TDP-43 toxicity. Yeast cells in which Dbr1 is deleted are resistant to TDP-43 toxicity. Dbr1 inhibition in mammalian cells is also sufficient to protect against TDP-43 cytotoxicity. Here, we review this recent discovery, highlighting future approaches aimed at extending these studies and pursuing Dbr1 as a novel therapeutic target for ALS.
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spelling pubmed-39330502014-07-07 Yeast genetic screen reveals novel therapeutic strategy for ALS Figley, Matthew D. Gitler, Aaron D. Rare Dis Addendum Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by a selective loss of motor neurons. There is no cure and few effective treatments. The RNA-binding protein TDP-43 contributes to the pathogenesis of ALS. TDP-43 is depleted from the nucleus and accumulates in cytoplasmic aggregates in the degenerating neurons and glia of most ALS patients. Furthermore, mutations in the TDP-43 gene cause rare familial and sporadic forms of the disease. Thus, therapeutic strategies targeting TDP-43 may be efficacious. We have used the yeast model system to identify the mechanisms by which TDP-43 aggregation contributes to ALS and to identify approaches to protect cells from the toxic effects of TDP-43 aggregation. Using an unbiased yeast genetic screen we discovered Dbr1 as a potent suppressor of TDP-43 toxicity. Yeast cells in which Dbr1 is deleted are resistant to TDP-43 toxicity. Dbr1 inhibition in mammalian cells is also sufficient to protect against TDP-43 cytotoxicity. Here, we review this recent discovery, highlighting future approaches aimed at extending these studies and pursuing Dbr1 as a novel therapeutic target for ALS. Landes Bioscience 2013-03-27 /pmc/articles/PMC3933050/ /pubmed/25002991 http://dx.doi.org/10.4161/rdis.24420 Text en Copyright © 2013 Landes Bioscience http://creativecommons.org/licenses/by-nc/3.0/ This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.
spellingShingle Addendum
Figley, Matthew D.
Gitler, Aaron D.
Yeast genetic screen reveals novel therapeutic strategy for ALS
title Yeast genetic screen reveals novel therapeutic strategy for ALS
title_full Yeast genetic screen reveals novel therapeutic strategy for ALS
title_fullStr Yeast genetic screen reveals novel therapeutic strategy for ALS
title_full_unstemmed Yeast genetic screen reveals novel therapeutic strategy for ALS
title_short Yeast genetic screen reveals novel therapeutic strategy for ALS
title_sort yeast genetic screen reveals novel therapeutic strategy for als
topic Addendum
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933050/
https://www.ncbi.nlm.nih.gov/pubmed/25002991
http://dx.doi.org/10.4161/rdis.24420
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