Cargando…
C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression
Expansion of an intronic (GGGGCC)(n) repeat region within the C9orf72 gene is a main cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). A hallmark of c9ALS/FTD is the accumulation of misprocessed RNAs, which are often targets of cellular RNA surveillance. Here,...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335171/ https://www.ncbi.nlm.nih.gov/pubmed/32620797 http://dx.doi.org/10.1038/s41467-020-17129-0 |
_version_ | 1783554087467352064 |
---|---|
author | Sun, Yu Eshov, Aziz Zhou, Jeffrey Isiktas, Atagun U. Guo, Junjie U. |
author_facet | Sun, Yu Eshov, Aziz Zhou, Jeffrey Isiktas, Atagun U. Guo, Junjie U. |
author_sort | Sun, Yu |
collection | PubMed |
description | Expansion of an intronic (GGGGCC)(n) repeat region within the C9orf72 gene is a main cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). A hallmark of c9ALS/FTD is the accumulation of misprocessed RNAs, which are often targets of cellular RNA surveillance. Here, we show that RNA decay mechanisms involving upstream frameshift 1 (UPF1), including nonsense-mediated decay (NMD), are inhibited in c9ALS/FTD brains and in cultured cells expressing either of two arginine-rich dipeptide repeats (R-DPRs), poly(GR) and poly(PR). Mechanistically, although R-DPRs cause the recruitment of UPF1 to stress granules, stress granule formation is independent of NMD inhibition. Instead, NMD inhibition is primarily a result from global translational repression caused by R-DPRs. Overexpression of UPF1, but none of its NMD-deficient mutants, enhanced the survival of neurons treated by R-DPRs, suggesting that R-DPRs cause neurotoxicity in part by inhibiting cellular RNA surveillance. |
format | Online Article Text |
id | pubmed-7335171 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-73351712020-07-09 C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression Sun, Yu Eshov, Aziz Zhou, Jeffrey Isiktas, Atagun U. Guo, Junjie U. Nat Commun Article Expansion of an intronic (GGGGCC)(n) repeat region within the C9orf72 gene is a main cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). A hallmark of c9ALS/FTD is the accumulation of misprocessed RNAs, which are often targets of cellular RNA surveillance. Here, we show that RNA decay mechanisms involving upstream frameshift 1 (UPF1), including nonsense-mediated decay (NMD), are inhibited in c9ALS/FTD brains and in cultured cells expressing either of two arginine-rich dipeptide repeats (R-DPRs), poly(GR) and poly(PR). Mechanistically, although R-DPRs cause the recruitment of UPF1 to stress granules, stress granule formation is independent of NMD inhibition. Instead, NMD inhibition is primarily a result from global translational repression caused by R-DPRs. Overexpression of UPF1, but none of its NMD-deficient mutants, enhanced the survival of neurons treated by R-DPRs, suggesting that R-DPRs cause neurotoxicity in part by inhibiting cellular RNA surveillance. Nature Publishing Group UK 2020-07-03 /pmc/articles/PMC7335171/ /pubmed/32620797 http://dx.doi.org/10.1038/s41467-020-17129-0 Text en © The Author(s) 2020, corrected publication 2022 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Sun, Yu Eshov, Aziz Zhou, Jeffrey Isiktas, Atagun U. Guo, Junjie U. C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression |
title | C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression |
title_full | C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression |
title_fullStr | C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression |
title_full_unstemmed | C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression |
title_short | C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression |
title_sort | c9orf72 arginine-rich dipeptide repeats inhibit upf1-mediated rna decay via translational repression |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335171/ https://www.ncbi.nlm.nih.gov/pubmed/32620797 http://dx.doi.org/10.1038/s41467-020-17129-0 |
work_keys_str_mv | AT sunyu c9orf72argininerichdipeptiderepeatsinhibitupf1mediatedrnadecayviatranslationalrepression AT eshovaziz c9orf72argininerichdipeptiderepeatsinhibitupf1mediatedrnadecayviatranslationalrepression AT zhoujeffrey c9orf72argininerichdipeptiderepeatsinhibitupf1mediatedrnadecayviatranslationalrepression AT isiktasatagunu c9orf72argininerichdipeptiderepeatsinhibitupf1mediatedrnadecayviatranslationalrepression AT guojunjieu c9orf72argininerichdipeptiderepeatsinhibitupf1mediatedrnadecayviatranslationalrepression |