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Aberrant activation of non-coding RNA targets of transcriptional elongation complexes contributes to TDP-43 toxicity

TDP-43 is the major disease protein associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-TDP). Here we identify the transcriptional elongation factor Ell—a shared component of little elongation complex (LEC) and super elongatio...

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Autores principales: Chung, Chia-Yu, Berson, Amit, Kennerdell, Jason R., Sartoris, Ashley, Unger, Travis, Porta, Sílvia, Kim, Hyung-Jun, Smith, Edwin R., Shilatifard, Ali, Van Deerlin, Vivianna, Lee, Virginia M.-Y., Chen-Plotkin, Alice, Bonini, Nancy M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199344/
https://www.ncbi.nlm.nih.gov/pubmed/30353006
http://dx.doi.org/10.1038/s41467-018-06543-0
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author Chung, Chia-Yu
Berson, Amit
Kennerdell, Jason R.
Sartoris, Ashley
Unger, Travis
Porta, Sílvia
Kim, Hyung-Jun
Smith, Edwin R.
Shilatifard, Ali
Van Deerlin, Vivianna
Lee, Virginia M.-Y.
Chen-Plotkin, Alice
Bonini, Nancy M.
author_facet Chung, Chia-Yu
Berson, Amit
Kennerdell, Jason R.
Sartoris, Ashley
Unger, Travis
Porta, Sílvia
Kim, Hyung-Jun
Smith, Edwin R.
Shilatifard, Ali
Van Deerlin, Vivianna
Lee, Virginia M.-Y.
Chen-Plotkin, Alice
Bonini, Nancy M.
author_sort Chung, Chia-Yu
collection PubMed
description TDP-43 is the major disease protein associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-TDP). Here we identify the transcriptional elongation factor Ell—a shared component of little elongation complex (LEC) and super elongation complex (SEC)—as a strong modifier of TDP-43-mediated neurodegeneration. Our data indicate select targets of LEC and SEC become upregulated in the fly ALS/FTLD-TDP model. Among them, U12 snRNA and a stress-induced long non-coding RNA Hsrω, functionally contribute to TDP-43-mediated degeneration. We extend the findings of Hsrω, which we identify as a chromosomal target of TDP-43, to show that the human orthologue Sat III is elevated in a human cellular disease model and FTLD-TDP patient tissue. We further demonstrate an interaction between TDP-43 and human ELL2 by co-immunoprecipitation from human cells. These findings reveal important roles of Ell-complexes LEC and SEC in TDP-43-associated toxicity, providing potential therapeutic insight for TDP-43-associated neurodegeneration.
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spelling pubmed-61993442018-10-25 Aberrant activation of non-coding RNA targets of transcriptional elongation complexes contributes to TDP-43 toxicity Chung, Chia-Yu Berson, Amit Kennerdell, Jason R. Sartoris, Ashley Unger, Travis Porta, Sílvia Kim, Hyung-Jun Smith, Edwin R. Shilatifard, Ali Van Deerlin, Vivianna Lee, Virginia M.-Y. Chen-Plotkin, Alice Bonini, Nancy M. Nat Commun Article TDP-43 is the major disease protein associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-TDP). Here we identify the transcriptional elongation factor Ell—a shared component of little elongation complex (LEC) and super elongation complex (SEC)—as a strong modifier of TDP-43-mediated neurodegeneration. Our data indicate select targets of LEC and SEC become upregulated in the fly ALS/FTLD-TDP model. Among them, U12 snRNA and a stress-induced long non-coding RNA Hsrω, functionally contribute to TDP-43-mediated degeneration. We extend the findings of Hsrω, which we identify as a chromosomal target of TDP-43, to show that the human orthologue Sat III is elevated in a human cellular disease model and FTLD-TDP patient tissue. We further demonstrate an interaction between TDP-43 and human ELL2 by co-immunoprecipitation from human cells. These findings reveal important roles of Ell-complexes LEC and SEC in TDP-43-associated toxicity, providing potential therapeutic insight for TDP-43-associated neurodegeneration. Nature Publishing Group UK 2018-10-23 /pmc/articles/PMC6199344/ /pubmed/30353006 http://dx.doi.org/10.1038/s41467-018-06543-0 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Chung, Chia-Yu
Berson, Amit
Kennerdell, Jason R.
Sartoris, Ashley
Unger, Travis
Porta, Sílvia
Kim, Hyung-Jun
Smith, Edwin R.
Shilatifard, Ali
Van Deerlin, Vivianna
Lee, Virginia M.-Y.
Chen-Plotkin, Alice
Bonini, Nancy M.
Aberrant activation of non-coding RNA targets of transcriptional elongation complexes contributes to TDP-43 toxicity
title Aberrant activation of non-coding RNA targets of transcriptional elongation complexes contributes to TDP-43 toxicity
title_full Aberrant activation of non-coding RNA targets of transcriptional elongation complexes contributes to TDP-43 toxicity
title_fullStr Aberrant activation of non-coding RNA targets of transcriptional elongation complexes contributes to TDP-43 toxicity
title_full_unstemmed Aberrant activation of non-coding RNA targets of transcriptional elongation complexes contributes to TDP-43 toxicity
title_short Aberrant activation of non-coding RNA targets of transcriptional elongation complexes contributes to TDP-43 toxicity
title_sort aberrant activation of non-coding rna targets of transcriptional elongation complexes contributes to tdp-43 toxicity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199344/
https://www.ncbi.nlm.nih.gov/pubmed/30353006
http://dx.doi.org/10.1038/s41467-018-06543-0
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