Isoform-Specific Reduction of the Basic Helix-Loop-Helix Transcription Factor TCF4 Levels in Huntington's Disease

Huntington's disease (HD) is an inherited neurodegenerative disorder with onset of characteristic motor symptoms at midlife, preceded by subtle cognitive and behavioral disturbances. Transcriptional dysregulation emerges early in the disease course and is considered central to HD pathogenesis....

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Autores: Nurm, Kaja, Sepp, Mari, Castany Pladevall, Carla, Creus Muncunill, Jordi, Tuvikene, Jürgen, Sirp, Alex, Vihma, Hanna, Blake, Derek J., Pérez Navarro, Esther, Timmusk, Tönis
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/183540
Acceso en línea:https://hdl.handle.net/2445/183540
Access Level:acceso abierto
Palabra clave:Corea de Huntington
Transcripció genètica
Huntington's chorea
Genetic transcription
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spelling Isoform-Specific Reduction of the Basic Helix-Loop-Helix Transcription Factor TCF4 Levels in Huntington's DiseaseNurm, KajaSepp, MariCastany Pladevall, CarlaCreus Muncunill, JordiTuvikene, JürgenSirp, AlexVihma, HannaBlake, Derek J.Pérez Navarro, EstherTimmusk, TönisCorea de HuntingtonTranscripció genèticaHuntington's choreaGenetic transcriptionHuntington's disease (HD) is an inherited neurodegenerative disorder with onset of characteristic motor symptoms at midlife, preceded by subtle cognitive and behavioral disturbances. Transcriptional dysregulation emerges early in the disease course and is considered central to HD pathogenesis. Using wild-type (wt) and HD knock-in mouse striatal cell lines we observed a HD genotype-dependent reduction in the protein levels of transcription factor 4 (TCF4), a member of the basic helix-loop-helix (bHLH) family with critical roles in brain development and function. We characterized mouse Tcf4 gene structure and expression of alternative mRNAs and protein isoforms in cell-based models of HD, and in four different brain regions of male transgenic HD mice (R6/1) from young to mature adulthood. The largest decrease in the levels of TCF4 at mRNA and specific protein isoforms were detected in the R6/1 mouse hippocampus. Translating this finding to human disease, we found reduced expression of long TCF4 isoforms in the postmortem hippocampal CA1 area and in the cerebral cortex of HD patients. Additionally, TCF4 protein isoforms showed differential synergism with the proneural transcription factor ASCL1 in activating reporter gene transcription in hippocampal and cortical cultured neurons. Induction of neuronal activity increased these synergistic effects in hippocampal but not in cortical neurons, suggesting brain region-dependent differences in TCF4 functions. Collectively, this study demonstrates isoform-specific changes in TCF4 expression in HD that could contribute to the progressive impairment of transcriptional regulation and neuronal function in this disease.The Society for Neuroscience2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/183540Articles publicats en revistes (Biomedicina)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1523/ENEURO.0197-21.2021eNeuro, 2021, vol. 8, num. 5https://doi.org/10.1523/ENEURO.0197-21.2021cc-by (c) Nurm, Kaja et al., 2021https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1835402026-05-27T06:46:51Z
dc.title.none.fl_str_mv Isoform-Specific Reduction of the Basic Helix-Loop-Helix Transcription Factor TCF4 Levels in Huntington's Disease
title Isoform-Specific Reduction of the Basic Helix-Loop-Helix Transcription Factor TCF4 Levels in Huntington's Disease
spellingShingle Isoform-Specific Reduction of the Basic Helix-Loop-Helix Transcription Factor TCF4 Levels in Huntington's Disease
Nurm, Kaja
Corea de Huntington
Transcripció genètica
Huntington's chorea
Genetic transcription
title_short Isoform-Specific Reduction of the Basic Helix-Loop-Helix Transcription Factor TCF4 Levels in Huntington's Disease
title_full Isoform-Specific Reduction of the Basic Helix-Loop-Helix Transcription Factor TCF4 Levels in Huntington's Disease
title_fullStr Isoform-Specific Reduction of the Basic Helix-Loop-Helix Transcription Factor TCF4 Levels in Huntington's Disease
title_full_unstemmed Isoform-Specific Reduction of the Basic Helix-Loop-Helix Transcription Factor TCF4 Levels in Huntington's Disease
title_sort Isoform-Specific Reduction of the Basic Helix-Loop-Helix Transcription Factor TCF4 Levels in Huntington's Disease
dc.creator.none.fl_str_mv Nurm, Kaja
Sepp, Mari
Castany Pladevall, Carla
Creus Muncunill, Jordi
Tuvikene, Jürgen
Sirp, Alex
Vihma, Hanna
Blake, Derek J.
Pérez Navarro, Esther
Timmusk, Tönis
author Nurm, Kaja
author_facet Nurm, Kaja
Sepp, Mari
Castany Pladevall, Carla
Creus Muncunill, Jordi
Tuvikene, Jürgen
Sirp, Alex
Vihma, Hanna
Blake, Derek J.
Pérez Navarro, Esther
Timmusk, Tönis
author_role author
author2 Sepp, Mari
Castany Pladevall, Carla
Creus Muncunill, Jordi
Tuvikene, Jürgen
Sirp, Alex
Vihma, Hanna
Blake, Derek J.
Pérez Navarro, Esther
Timmusk, Tönis
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Corea de Huntington
Transcripció genètica
Huntington's chorea
Genetic transcription
topic Corea de Huntington
Transcripció genètica
Huntington's chorea
Genetic transcription
description Huntington's disease (HD) is an inherited neurodegenerative disorder with onset of characteristic motor symptoms at midlife, preceded by subtle cognitive and behavioral disturbances. Transcriptional dysregulation emerges early in the disease course and is considered central to HD pathogenesis. Using wild-type (wt) and HD knock-in mouse striatal cell lines we observed a HD genotype-dependent reduction in the protein levels of transcription factor 4 (TCF4), a member of the basic helix-loop-helix (bHLH) family with critical roles in brain development and function. We characterized mouse Tcf4 gene structure and expression of alternative mRNAs and protein isoforms in cell-based models of HD, and in four different brain regions of male transgenic HD mice (R6/1) from young to mature adulthood. The largest decrease in the levels of TCF4 at mRNA and specific protein isoforms were detected in the R6/1 mouse hippocampus. Translating this finding to human disease, we found reduced expression of long TCF4 isoforms in the postmortem hippocampal CA1 area and in the cerebral cortex of HD patients. Additionally, TCF4 protein isoforms showed differential synergism with the proneural transcription factor ASCL1 in activating reporter gene transcription in hippocampal and cortical cultured neurons. Induction of neuronal activity increased these synergistic effects in hippocampal but not in cortical neurons, suggesting brain region-dependent differences in TCF4 functions. Collectively, this study demonstrates isoform-specific changes in TCF4 expression in HD that could contribute to the progressive impairment of transcriptional regulation and neuronal function in this disease.
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/183540
url https://hdl.handle.net/2445/183540
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1523/ENEURO.0197-21.2021
eNeuro, 2021, vol. 8, num. 5
https://doi.org/10.1523/ENEURO.0197-21.2021
dc.rights.none.fl_str_mv cc-by (c) Nurm, Kaja et al., 2021
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Nurm, Kaja et al., 2021
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv The Society for Neuroscience
publisher.none.fl_str_mv The Society for Neuroscience
dc.source.none.fl_str_mv Articles publicats en revistes (Biomedicina)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301629

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