The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington’s disease patients

Abstract We have previously shown that exon 1 of the huntingtin gene does not always splice to exon 2 resulting in the production of a small polyadenylated mRNA (HTTexon1) that encodes the highly pathogenic exon 1 HTT protein. The level of this read-through product is proportional to CAG repeat leng...

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Autores principales:	Andreas Neueder, Christian Landles, Rhia Ghosh, David Howland, Richard H. Myers, Richard L. M. Faull, Sarah J. Tabrizi, Gillian P. Bates
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/880697bfb72a45d88a4cbeba52640f2d
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spelling	oai:doaj.org-article:880697bfb72a45d88a4cbeba52640f2d2021-12-02T16:06:40ZThe pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington’s disease patients10.1038/s41598-017-01510-z2045-2322https://doaj.org/article/880697bfb72a45d88a4cbeba52640f2d2017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01510-zhttps://doaj.org/toc/2045-2322Abstract We have previously shown that exon 1 of the huntingtin gene does not always splice to exon 2 resulting in the production of a small polyadenylated mRNA (HTTexon1) that encodes the highly pathogenic exon 1 HTT protein. The level of this read-through product is proportional to CAG repeat length and is present in all knock-in mouse models of Huntington’s disease (HD) with CAG lengths of 50 and above and in the YAC128 and BACHD mouse models, both of which express a copy of the human HTT gene. We have now developed specific protocols for the quantitative analysis of the transcript levels of HTTexon1 in human tissue and applied these to a series of fibroblast lines and post-mortem brain samples from individuals with either adult-onset or juvenile-onset HD. We found that the HTTexon1 mRNA is present in fibroblasts from juvenile HD patients and can also be readily detected in the sensory motor cortex, hippocampus and cerebellum of post-mortem brains from HD individuals, particularly in those with early onset disease. This finding will have important implications for strategies to lower mutant HTT levels in patients and the design of future therapeutics.Andreas NeuederChristian LandlesRhia GhoshDavid HowlandRichard H. MyersRichard L. M. FaullSarah J. TabriziGillian P. BatesNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Andreas Neueder Christian Landles Rhia Ghosh David Howland Richard H. Myers Richard L. M. Faull Sarah J. Tabrizi Gillian P. Bates The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington’s disease patients
description	Abstract We have previously shown that exon 1 of the huntingtin gene does not always splice to exon 2 resulting in the production of a small polyadenylated mRNA (HTTexon1) that encodes the highly pathogenic exon 1 HTT protein. The level of this read-through product is proportional to CAG repeat length and is present in all knock-in mouse models of Huntington’s disease (HD) with CAG lengths of 50 and above and in the YAC128 and BACHD mouse models, both of which express a copy of the human HTT gene. We have now developed specific protocols for the quantitative analysis of the transcript levels of HTTexon1 in human tissue and applied these to a series of fibroblast lines and post-mortem brain samples from individuals with either adult-onset or juvenile-onset HD. We found that the HTTexon1 mRNA is present in fibroblasts from juvenile HD patients and can also be readily detected in the sensory motor cortex, hippocampus and cerebellum of post-mortem brains from HD individuals, particularly in those with early onset disease. This finding will have important implications for strategies to lower mutant HTT levels in patients and the design of future therapeutics.
format	article
author	Andreas Neueder Christian Landles Rhia Ghosh David Howland Richard H. Myers Richard L. M. Faull Sarah J. Tabrizi Gillian P. Bates
author_facet	Andreas Neueder Christian Landles Rhia Ghosh David Howland Richard H. Myers Richard L. M. Faull Sarah J. Tabrizi Gillian P. Bates
author_sort	Andreas Neueder
title	The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington’s disease patients
title_short	The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington’s disease patients
title_full	The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington’s disease patients
title_fullStr	The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington’s disease patients
title_full_unstemmed	The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington’s disease patients
title_sort	pathogenic exon 1 htt protein is produced by incomplete splicing in huntington’s disease patients
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/880697bfb72a45d88a4cbeba52640f2d
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The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington’s disease patients

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