Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice

Neural cultures derived from Huntington's disease (HD) patient-derived induced pluripotent stem cells were used for 'omics' analyses to identify mechanisms underlying neurodegeneration. RNA-seq analysis identified genes in glutamate and GABA signaling, axonal guidance and calcium infl...

Descripción completa

Detalles Bibliográficos
Autores: Pardo Muñoz, Mònica, García-Díaz Barriga, Gerardo, Straccia, Marco, Sanders, Phil, Alberch i Vié, Jordi, 1959-, Canals i Coll, Josep M., HD iPSC Consortium
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2017
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/128042
Acceso en línea:https://hdl.handle.net/2445/128042
Access Level:acceso abierto
Palabra clave:Corea de Huntington
Huntington's chorea
id ES_f98d3ddce716a848670f0c6b4f6ee4e0
oai_identifier_str oai:recercat.cat:2445/128042
network_acronym_str ES
network_name_str España
repository_id_str
spelling Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and micePardo Muñoz, MònicaGarcía-Díaz Barriga, GerardoStraccia, MarcoSanders, PhilAlberch i Vié, Jordi, 1959-Canals i Coll, Josep M.HD iPSC ConsortiumCorea de HuntingtonHuntington's choreaNeural cultures derived from Huntington's disease (HD) patient-derived induced pluripotent stem cells were used for 'omics' analyses to identify mechanisms underlying neurodegeneration. RNA-seq analysis identified genes in glutamate and GABA signaling, axonal guidance and calcium influx whose expression was decreased in HD cultures. One-third of gene changes were in pathways regulating neuronal development and maturation. When mapped to stages of mouse striatal development, the profiles aligned with earlier embryonic stages of neuronal differentiation. We observed a strong correlation between HD-related histone marks, gene expression and unique peak profiles associated with dysregulated genes, suggesting a coordinated epigenetic program. Treatment with isoxazole-9, which targets key dysregulated pathways, led to amelioration of expanded polyglutamine repeat-associated phenotypes in neural cells and of cognitive impairment and synaptic pathology in HD model R6/2 mice. These data suggest that mutant huntingtin impairs neurodevelopmental pathways that could disrupt synaptic homeostasis and increase vulnerability to the pathologic consequence of expanded polyglutamine repeats over time.Nature Publishing Group2019201920172019info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion13 p.application/pdfhttps://hdl.handle.net/2445/128042Articles publicats en revistes (Biomedicina)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: https://doi.org/10.1038/nn.4532Nature Neuroscience, 2017, vol. 20, num. 5, p. 648-660https://doi.org/10.1038/nn.4532(c) Pardo Muñoz, Mònica et al., 2017info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1280422026-05-29T05:05:01Z
dc.title.none.fl_str_mv Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice
title Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice
spellingShingle Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice
Pardo Muñoz, Mònica
Corea de Huntington
Huntington's chorea
title_short Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice
title_full Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice
title_fullStr Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice
title_full_unstemmed Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice
title_sort Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice
dc.creator.none.fl_str_mv Pardo Muñoz, Mònica
García-Díaz Barriga, Gerardo
Straccia, Marco
Sanders, Phil
Alberch i Vié, Jordi, 1959-
Canals i Coll, Josep M.
HD iPSC Consortium
author Pardo Muñoz, Mònica
author_facet Pardo Muñoz, Mònica
García-Díaz Barriga, Gerardo
Straccia, Marco
Sanders, Phil
Alberch i Vié, Jordi, 1959-
Canals i Coll, Josep M.
HD iPSC Consortium
author_role author
author2 García-Díaz Barriga, Gerardo
Straccia, Marco
Sanders, Phil
Alberch i Vié, Jordi, 1959-
Canals i Coll, Josep M.
HD iPSC Consortium
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Corea de Huntington
Huntington's chorea
topic Corea de Huntington
Huntington's chorea
description Neural cultures derived from Huntington's disease (HD) patient-derived induced pluripotent stem cells were used for 'omics' analyses to identify mechanisms underlying neurodegeneration. RNA-seq analysis identified genes in glutamate and GABA signaling, axonal guidance and calcium influx whose expression was decreased in HD cultures. One-third of gene changes were in pathways regulating neuronal development and maturation. When mapped to stages of mouse striatal development, the profiles aligned with earlier embryonic stages of neuronal differentiation. We observed a strong correlation between HD-related histone marks, gene expression and unique peak profiles associated with dysregulated genes, suggesting a coordinated epigenetic program. Treatment with isoxazole-9, which targets key dysregulated pathways, led to amelioration of expanded polyglutamine repeat-associated phenotypes in neural cells and of cognitive impairment and synaptic pathology in HD model R6/2 mice. These data suggest that mutant huntingtin impairs neurodevelopmental pathways that could disrupt synaptic homeostasis and increase vulnerability to the pathologic consequence of expanded polyglutamine repeats over time.
publishDate 2017
dc.date.none.fl_str_mv 2017
2019
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/128042
url https://hdl.handle.net/2445/128042
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1038/nn.4532
Nature Neuroscience, 2017, vol. 20, num. 5, p. 648-660
https://doi.org/10.1038/nn.4532
dc.rights.none.fl_str_mv (c) Pardo Muñoz, Mònica et al., 2017
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Pardo Muñoz, Mònica et al., 2017
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 13 p.
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv Articles publicats en revistes (Biomedicina)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869425105388437504
score 15.812429

Similares en LA Referencia