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Multiple pathways of toxicity induced by C9orf72 dipeptide repeat aggregates and G(4)C(2) RNA in a cellular model

The most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia is a G(4)C(2) repeat expansion in the C9orf72 gene. This expansion gives rise to translation of aggregating dipeptide repeat (DPR) proteins, including poly-GA as the most abundant species. However, gain of t...

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Autores principales: Frottin, Frédéric, Pérez-Berlanga, Manuela, Hartl, F Ulrich, Hipp, Mark S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221807/
https://www.ncbi.nlm.nih.gov/pubmed/34161229
http://dx.doi.org/10.7554/eLife.62718
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author Frottin, Frédéric
Pérez-Berlanga, Manuela
Hartl, F Ulrich
Hipp, Mark S
author_facet Frottin, Frédéric
Pérez-Berlanga, Manuela
Hartl, F Ulrich
Hipp, Mark S
author_sort Frottin, Frédéric
collection PubMed
description The most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia is a G(4)C(2) repeat expansion in the C9orf72 gene. This expansion gives rise to translation of aggregating dipeptide repeat (DPR) proteins, including poly-GA as the most abundant species. However, gain of toxic function effects have been attributed to either the DPRs or the pathological G(4)C(2) RNA. Here, we analyzed in a cellular model the relative toxicity of DPRs and RNA. Cytoplasmic poly-GA aggregates, generated in the absence of G(4)C(2) RNA, interfered with nucleocytoplasmic protein transport, but had little effect on cell viability. In contrast, nuclear poly-GA was more toxic, impairing nucleolar protein quality control and protein biosynthesis. Production of the G(4)C(2) RNA strongly reduced viability independent of DPR translation and caused pronounced inhibition of nuclear mRNA export and protein biogenesis. Thus, while the toxic effects of G(4)C(2) RNA predominate in the cellular model used, DPRs exert additive effects that may contribute to pathology.
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spelling pubmed-82218072021-06-24 Multiple pathways of toxicity induced by C9orf72 dipeptide repeat aggregates and G(4)C(2) RNA in a cellular model Frottin, Frédéric Pérez-Berlanga, Manuela Hartl, F Ulrich Hipp, Mark S eLife Biochemistry and Chemical Biology The most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia is a G(4)C(2) repeat expansion in the C9orf72 gene. This expansion gives rise to translation of aggregating dipeptide repeat (DPR) proteins, including poly-GA as the most abundant species. However, gain of toxic function effects have been attributed to either the DPRs or the pathological G(4)C(2) RNA. Here, we analyzed in a cellular model the relative toxicity of DPRs and RNA. Cytoplasmic poly-GA aggregates, generated in the absence of G(4)C(2) RNA, interfered with nucleocytoplasmic protein transport, but had little effect on cell viability. In contrast, nuclear poly-GA was more toxic, impairing nucleolar protein quality control and protein biosynthesis. Production of the G(4)C(2) RNA strongly reduced viability independent of DPR translation and caused pronounced inhibition of nuclear mRNA export and protein biogenesis. Thus, while the toxic effects of G(4)C(2) RNA predominate in the cellular model used, DPRs exert additive effects that may contribute to pathology. eLife Sciences Publications, Ltd 2021-06-23 /pmc/articles/PMC8221807/ /pubmed/34161229 http://dx.doi.org/10.7554/eLife.62718 Text en © 2021, Frottin et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Frottin, Frédéric
Pérez-Berlanga, Manuela
Hartl, F Ulrich
Hipp, Mark S
Multiple pathways of toxicity induced by C9orf72 dipeptide repeat aggregates and G(4)C(2) RNA in a cellular model
title Multiple pathways of toxicity induced by C9orf72 dipeptide repeat aggregates and G(4)C(2) RNA in a cellular model
title_full Multiple pathways of toxicity induced by C9orf72 dipeptide repeat aggregates and G(4)C(2) RNA in a cellular model
title_fullStr Multiple pathways of toxicity induced by C9orf72 dipeptide repeat aggregates and G(4)C(2) RNA in a cellular model
title_full_unstemmed Multiple pathways of toxicity induced by C9orf72 dipeptide repeat aggregates and G(4)C(2) RNA in a cellular model
title_short Multiple pathways of toxicity induced by C9orf72 dipeptide repeat aggregates and G(4)C(2) RNA in a cellular model
title_sort multiple pathways of toxicity induced by c9orf72 dipeptide repeat aggregates and g(4)c(2) rna in a cellular model
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221807/
https://www.ncbi.nlm.nih.gov/pubmed/34161229
http://dx.doi.org/10.7554/eLife.62718
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