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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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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. |
format | Online Article Text |
id | pubmed-8221807 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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