Cargando…

Intron retention and nuclear loss of SFPQ are molecular hallmarks of ALS

Mutations causing amyotrophic lateral sclerosis (ALS) strongly implicate ubiquitously expressed regulators of RNA processing. To understand the molecular impact of ALS-causing mutations on neuronal development and disease, we analysed transcriptomes during in vitro differentiation of motor neurons (...

Descripción completa

Detalles Bibliográficos
Autores principales: Luisier, Raphaelle, Tyzack, Giulia E., Hall, Claire E., Mitchell, Jamie S., Devine, Helen, Taha, Doaa M., Malik, Bilal, Meyer, Ione, Greensmith, Linda, Newcombe, Jia, Ule, Jernej, Luscombe, Nicholas M., Patani, Rickie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964114/
https://www.ncbi.nlm.nih.gov/pubmed/29789581
http://dx.doi.org/10.1038/s41467-018-04373-8
_version_ 1783325117504290816
author Luisier, Raphaelle
Tyzack, Giulia E.
Hall, Claire E.
Mitchell, Jamie S.
Devine, Helen
Taha, Doaa M.
Malik, Bilal
Meyer, Ione
Greensmith, Linda
Newcombe, Jia
Ule, Jernej
Luscombe, Nicholas M.
Patani, Rickie
author_facet Luisier, Raphaelle
Tyzack, Giulia E.
Hall, Claire E.
Mitchell, Jamie S.
Devine, Helen
Taha, Doaa M.
Malik, Bilal
Meyer, Ione
Greensmith, Linda
Newcombe, Jia
Ule, Jernej
Luscombe, Nicholas M.
Patani, Rickie
author_sort Luisier, Raphaelle
collection PubMed
description Mutations causing amyotrophic lateral sclerosis (ALS) strongly implicate ubiquitously expressed regulators of RNA processing. To understand the molecular impact of ALS-causing mutations on neuronal development and disease, we analysed transcriptomes during in vitro differentiation of motor neurons (MNs) from human control and patient-specific VCP mutant induced-pluripotent stem cells (iPSCs). We identify increased intron retention (IR) as a dominant feature of the splicing programme during early neural differentiation. Importantly, IR occurs prematurely in VCP mutant cultures compared with control counterparts. These aberrant IR events are also seen in independent RNAseq data sets from SOD1- and FUS-mutant MNs. The most significant IR is seen in the SFPQ transcript. The SFPQ protein binds extensively to its retained intron, exhibits lower nuclear abundance in VCP mutant cultures and is lost from nuclei of MNs in mouse models and human sporadic ALS. Collectively, we demonstrate SFPQ IR and nuclear loss as molecular hallmarks of familial and sporadic ALS.
format Online
Article
Text
id pubmed-5964114
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-59641142018-05-24 Intron retention and nuclear loss of SFPQ are molecular hallmarks of ALS Luisier, Raphaelle Tyzack, Giulia E. Hall, Claire E. Mitchell, Jamie S. Devine, Helen Taha, Doaa M. Malik, Bilal Meyer, Ione Greensmith, Linda Newcombe, Jia Ule, Jernej Luscombe, Nicholas M. Patani, Rickie Nat Commun Article Mutations causing amyotrophic lateral sclerosis (ALS) strongly implicate ubiquitously expressed regulators of RNA processing. To understand the molecular impact of ALS-causing mutations on neuronal development and disease, we analysed transcriptomes during in vitro differentiation of motor neurons (MNs) from human control and patient-specific VCP mutant induced-pluripotent stem cells (iPSCs). We identify increased intron retention (IR) as a dominant feature of the splicing programme during early neural differentiation. Importantly, IR occurs prematurely in VCP mutant cultures compared with control counterparts. These aberrant IR events are also seen in independent RNAseq data sets from SOD1- and FUS-mutant MNs. The most significant IR is seen in the SFPQ transcript. The SFPQ protein binds extensively to its retained intron, exhibits lower nuclear abundance in VCP mutant cultures and is lost from nuclei of MNs in mouse models and human sporadic ALS. Collectively, we demonstrate SFPQ IR and nuclear loss as molecular hallmarks of familial and sporadic ALS. Nature Publishing Group UK 2018-05-22 /pmc/articles/PMC5964114/ /pubmed/29789581 http://dx.doi.org/10.1038/s41467-018-04373-8 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
Luisier, Raphaelle
Tyzack, Giulia E.
Hall, Claire E.
Mitchell, Jamie S.
Devine, Helen
Taha, Doaa M.
Malik, Bilal
Meyer, Ione
Greensmith, Linda
Newcombe, Jia
Ule, Jernej
Luscombe, Nicholas M.
Patani, Rickie
Intron retention and nuclear loss of SFPQ are molecular hallmarks of ALS
title Intron retention and nuclear loss of SFPQ are molecular hallmarks of ALS
title_full Intron retention and nuclear loss of SFPQ are molecular hallmarks of ALS
title_fullStr Intron retention and nuclear loss of SFPQ are molecular hallmarks of ALS
title_full_unstemmed Intron retention and nuclear loss of SFPQ are molecular hallmarks of ALS
title_short Intron retention and nuclear loss of SFPQ are molecular hallmarks of ALS
title_sort intron retention and nuclear loss of sfpq are molecular hallmarks of als
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964114/
https://www.ncbi.nlm.nih.gov/pubmed/29789581
http://dx.doi.org/10.1038/s41467-018-04373-8
work_keys_str_mv AT luisierraphaelle intronretentionandnuclearlossofsfpqaremolecularhallmarksofals
AT tyzackgiuliae intronretentionandnuclearlossofsfpqaremolecularhallmarksofals
AT hallclairee intronretentionandnuclearlossofsfpqaremolecularhallmarksofals
AT mitchelljamies intronretentionandnuclearlossofsfpqaremolecularhallmarksofals
AT devinehelen intronretentionandnuclearlossofsfpqaremolecularhallmarksofals
AT tahadoaam intronretentionandnuclearlossofsfpqaremolecularhallmarksofals
AT malikbilal intronretentionandnuclearlossofsfpqaremolecularhallmarksofals
AT meyerione intronretentionandnuclearlossofsfpqaremolecularhallmarksofals
AT greensmithlinda intronretentionandnuclearlossofsfpqaremolecularhallmarksofals
AT newcombejia intronretentionandnuclearlossofsfpqaremolecularhallmarksofals
AT ulejernej intronretentionandnuclearlossofsfpqaremolecularhallmarksofals
AT luscombenicholasm intronretentionandnuclearlossofsfpqaremolecularhallmarksofals
AT patanirickie intronretentionandnuclearlossofsfpqaremolecularhallmarksofals