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The evolutionary history of the polyQ tract in huntingtin sheds light on its functional pro-neural activities

Huntington’s disease is caused by a pathologically long (>35) CAG repeat located in the first exon of the Huntingtin gene (HTT). While pathologically expanded CAG repeats are the focus of extensive investigations, non-pathogenic CAG tracts in protein-coding genes are less well characterized. Here...

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Autores principales: Iennaco, Raffaele, Formenti, Giulio, Trovesi, Camilla, Rossi, Riccardo Lorenzo, Zuccato, Chiara, Lischetti, Tiziana, Bocchi, Vittoria Dickinson, Scolz, Andrea, Martínez-Labarga, Cristina, Rickards, Olga, Pacifico, Michela, Crottini, Angelica, Møller, Anders Pape, Chen, Richard Zhenghuan, Vogt, Thomas Francis, Pavesi, Giulio, Horner, David Stephen, Saino, Nicola, Cattaneo, Elena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8817008/
https://www.ncbi.nlm.nih.gov/pubmed/34974533
http://dx.doi.org/10.1038/s41418-021-00914-9
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author Iennaco, Raffaele
Formenti, Giulio
Trovesi, Camilla
Rossi, Riccardo Lorenzo
Zuccato, Chiara
Lischetti, Tiziana
Bocchi, Vittoria Dickinson
Scolz, Andrea
Martínez-Labarga, Cristina
Rickards, Olga
Pacifico, Michela
Crottini, Angelica
Møller, Anders Pape
Chen, Richard Zhenghuan
Vogt, Thomas Francis
Pavesi, Giulio
Horner, David Stephen
Saino, Nicola
Cattaneo, Elena
author_facet Iennaco, Raffaele
Formenti, Giulio
Trovesi, Camilla
Rossi, Riccardo Lorenzo
Zuccato, Chiara
Lischetti, Tiziana
Bocchi, Vittoria Dickinson
Scolz, Andrea
Martínez-Labarga, Cristina
Rickards, Olga
Pacifico, Michela
Crottini, Angelica
Møller, Anders Pape
Chen, Richard Zhenghuan
Vogt, Thomas Francis
Pavesi, Giulio
Horner, David Stephen
Saino, Nicola
Cattaneo, Elena
author_sort Iennaco, Raffaele
collection PubMed
description Huntington’s disease is caused by a pathologically long (>35) CAG repeat located in the first exon of the Huntingtin gene (HTT). While pathologically expanded CAG repeats are the focus of extensive investigations, non-pathogenic CAG tracts in protein-coding genes are less well characterized. Here, we investigated the function and evolution of the physiological CAG tract in the HTT gene. We show that the poly-glutamine (polyQ) tract encoded by CAGs in the huntingtin protein (HTT) is under purifying selection and subjected to stronger selective pressures than CAG-encoded polyQ tracts in other proteins. For natural selection to operate, the polyQ must perform a function. By combining genome-edited mouse embryonic stem cells and cell assays, we show that small variations in HTT polyQ lengths significantly correlate with cells’ neurogenic potential and with changes in the gene transcription network governing neuronal function. We conclude that during evolution natural selection promotes the conservation and purity of the CAG-encoded polyQ tract and that small increases in its physiological length influence neural functions of HTT. We propose that these changes in HTT polyQ length contribute to evolutionary fitness including potentially to the development of a more complex nervous system.
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spelling pubmed-88170082022-02-16 The evolutionary history of the polyQ tract in huntingtin sheds light on its functional pro-neural activities Iennaco, Raffaele Formenti, Giulio Trovesi, Camilla Rossi, Riccardo Lorenzo Zuccato, Chiara Lischetti, Tiziana Bocchi, Vittoria Dickinson Scolz, Andrea Martínez-Labarga, Cristina Rickards, Olga Pacifico, Michela Crottini, Angelica Møller, Anders Pape Chen, Richard Zhenghuan Vogt, Thomas Francis Pavesi, Giulio Horner, David Stephen Saino, Nicola Cattaneo, Elena Cell Death Differ Article Huntington’s disease is caused by a pathologically long (>35) CAG repeat located in the first exon of the Huntingtin gene (HTT). While pathologically expanded CAG repeats are the focus of extensive investigations, non-pathogenic CAG tracts in protein-coding genes are less well characterized. Here, we investigated the function and evolution of the physiological CAG tract in the HTT gene. We show that the poly-glutamine (polyQ) tract encoded by CAGs in the huntingtin protein (HTT) is under purifying selection and subjected to stronger selective pressures than CAG-encoded polyQ tracts in other proteins. For natural selection to operate, the polyQ must perform a function. By combining genome-edited mouse embryonic stem cells and cell assays, we show that small variations in HTT polyQ lengths significantly correlate with cells’ neurogenic potential and with changes in the gene transcription network governing neuronal function. We conclude that during evolution natural selection promotes the conservation and purity of the CAG-encoded polyQ tract and that small increases in its physiological length influence neural functions of HTT. We propose that these changes in HTT polyQ length contribute to evolutionary fitness including potentially to the development of a more complex nervous system. Nature Publishing Group UK 2022-01-01 2022-02 /pmc/articles/PMC8817008/ /pubmed/34974533 http://dx.doi.org/10.1038/s41418-021-00914-9 Text en © The Author(s) 2021 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
Iennaco, Raffaele
Formenti, Giulio
Trovesi, Camilla
Rossi, Riccardo Lorenzo
Zuccato, Chiara
Lischetti, Tiziana
Bocchi, Vittoria Dickinson
Scolz, Andrea
Martínez-Labarga, Cristina
Rickards, Olga
Pacifico, Michela
Crottini, Angelica
Møller, Anders Pape
Chen, Richard Zhenghuan
Vogt, Thomas Francis
Pavesi, Giulio
Horner, David Stephen
Saino, Nicola
Cattaneo, Elena
The evolutionary history of the polyQ tract in huntingtin sheds light on its functional pro-neural activities
title The evolutionary history of the polyQ tract in huntingtin sheds light on its functional pro-neural activities
title_full The evolutionary history of the polyQ tract in huntingtin sheds light on its functional pro-neural activities
title_fullStr The evolutionary history of the polyQ tract in huntingtin sheds light on its functional pro-neural activities
title_full_unstemmed The evolutionary history of the polyQ tract in huntingtin sheds light on its functional pro-neural activities
title_short The evolutionary history of the polyQ tract in huntingtin sheds light on its functional pro-neural activities
title_sort evolutionary history of the polyq tract in huntingtin sheds light on its functional pro-neural activities
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8817008/
https://www.ncbi.nlm.nih.gov/pubmed/34974533
http://dx.doi.org/10.1038/s41418-021-00914-9
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