Silencing Srsf6 does not modulate incomplete splicing of the huntingtin gene in Huntington’s disease models

Abstract We have previously shown that the incomplete splicing of exon 1 to exon 2 of the HTT gene results in the production of a small polyadenylated transcript (Httexon1) that encodes the highly pathogenic exon 1 HTT protein. There is evidence to suggest that the splicing factor SRSF6 is involved...

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Autores principales:	Michael A. Mason, Casandra Gomez-Paredes, Kirupa Sathasivam, Andreas Neueder, Aikaterini-Smaragdi Papadopoulou, Gillian P. Bates
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/75c2b3b27ebe45d08097db3813c6768f
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spelling	oai:doaj.org-article:75c2b3b27ebe45d08097db3813c6768f2021-12-02T16:45:46ZSilencing Srsf6 does not modulate incomplete splicing of the huntingtin gene in Huntington’s disease models10.1038/s41598-020-71111-w2045-2322https://doaj.org/article/75c2b3b27ebe45d08097db3813c6768f2020-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-71111-whttps://doaj.org/toc/2045-2322Abstract We have previously shown that the incomplete splicing of exon 1 to exon 2 of the HTT gene results in the production of a small polyadenylated transcript (Httexon1) that encodes the highly pathogenic exon 1 HTT protein. There is evidence to suggest that the splicing factor SRSF6 is involved in the mechanism that underlies this aberrant splicing event. Therefore, we set out to test this hypothesis, by manipulating SRSF6 levels in Huntington’s disease models in which an expanded CAG repeat had been knocked in to the endogenous Htt gene. We began by generating mice that were knocked out for Srsf6, and demonstrated that reduction of SRSF6 to 50% of wild type levels had no effect on incomplete splicing in zQ175 knockin mice. We found that nullizygosity for Srsf6 was embryonic lethal, and therefore, to decrease SRSF6 levels further, we established mouse embryonic fibroblasts (MEFs) from wild type, zQ175, and zQ175::Srsf6 +/− mice and transfected them with an Srsf6 siRNA. The incomplete splicing of Htt was recapitulated in the MEFs and we demonstrated that ablation of SRSF6 did not modulate the levels of the Httexon1 transcript. We conclude that SRSF6 is not required for the incomplete splicing of HTT in Huntington’s disease.Michael A. MasonCasandra Gomez-ParedesKirupa SathasivamAndreas NeuederAikaterini-Smaragdi PapadopoulouGillian P. BatesNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-12 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Michael A. Mason Casandra Gomez-Paredes Kirupa Sathasivam Andreas Neueder Aikaterini-Smaragdi Papadopoulou Gillian P. Bates Silencing Srsf6 does not modulate incomplete splicing of the huntingtin gene in Huntington’s disease models
description	Abstract We have previously shown that the incomplete splicing of exon 1 to exon 2 of the HTT gene results in the production of a small polyadenylated transcript (Httexon1) that encodes the highly pathogenic exon 1 HTT protein. There is evidence to suggest that the splicing factor SRSF6 is involved in the mechanism that underlies this aberrant splicing event. Therefore, we set out to test this hypothesis, by manipulating SRSF6 levels in Huntington’s disease models in which an expanded CAG repeat had been knocked in to the endogenous Htt gene. We began by generating mice that were knocked out for Srsf6, and demonstrated that reduction of SRSF6 to 50% of wild type levels had no effect on incomplete splicing in zQ175 knockin mice. We found that nullizygosity for Srsf6 was embryonic lethal, and therefore, to decrease SRSF6 levels further, we established mouse embryonic fibroblasts (MEFs) from wild type, zQ175, and zQ175::Srsf6 +/− mice and transfected them with an Srsf6 siRNA. The incomplete splicing of Htt was recapitulated in the MEFs and we demonstrated that ablation of SRSF6 did not modulate the levels of the Httexon1 transcript. We conclude that SRSF6 is not required for the incomplete splicing of HTT in Huntington’s disease.
format	article
author	Michael A. Mason Casandra Gomez-Paredes Kirupa Sathasivam Andreas Neueder Aikaterini-Smaragdi Papadopoulou Gillian P. Bates
author_facet	Michael A. Mason Casandra Gomez-Paredes Kirupa Sathasivam Andreas Neueder Aikaterini-Smaragdi Papadopoulou Gillian P. Bates
author_sort	Michael A. Mason
title	Silencing Srsf6 does not modulate incomplete splicing of the huntingtin gene in Huntington’s disease models
title_short	Silencing Srsf6 does not modulate incomplete splicing of the huntingtin gene in Huntington’s disease models
title_full	Silencing Srsf6 does not modulate incomplete splicing of the huntingtin gene in Huntington’s disease models
title_fullStr	Silencing Srsf6 does not modulate incomplete splicing of the huntingtin gene in Huntington’s disease models
title_full_unstemmed	Silencing Srsf6 does not modulate incomplete splicing of the huntingtin gene in Huntington’s disease models
title_sort	silencing srsf6 does not modulate incomplete splicing of the huntingtin gene in huntington’s disease models
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/75c2b3b27ebe45d08097db3813c6768f
work_keys_str_mv	AT michaelamason silencingsrsf6doesnotmodulateincompletesplicingofthehuntingtingeneinhuntingtonsdiseasemodels AT casandragomezparedes silencingsrsf6doesnotmodulateincompletesplicingofthehuntingtingeneinhuntingtonsdiseasemodels AT kirupasathasivam silencingsrsf6doesnotmodulateincompletesplicingofthehuntingtingeneinhuntingtonsdiseasemodels AT andreasneueder silencingsrsf6doesnotmodulateincompletesplicingofthehuntingtingeneinhuntingtonsdiseasemodels AT aikaterinismaragdipapadopoulou silencingsrsf6doesnotmodulateincompletesplicingofthehuntingtingeneinhuntingtonsdiseasemodels AT gillianpbates silencingsrsf6doesnotmodulateincompletesplicingofthehuntingtingeneinhuntingtonsdiseasemodels
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Silencing Srsf6 does not modulate incomplete splicing of the huntingtin gene in Huntington’s disease models

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