Pharmacogenetic Modulation of STEP improves motor and cognitive function in a mouse model of Huntington's disease.

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an expansion of a CAG repeat in the huntingtin (htt) gene, which results in an aberrant form of the protein (mhtt). This leads to motor and cognitive deficits associated with corticostriatal and hippocampal alteratio...

ver descrição completa

Detalhes bibliográficos
Autores: Garcia-Forn, Marta, Martínez Torres, Sara, García-Díaz Barriga, Gerardo, Alberch i Vié, Jordi, 1959-, Milà i Recasens, Montserrat, Azkona, Garikoitz, Pérez Navarro, Esther
Formato: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2018
País:España
Recursos: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:2445/184474
Acesso em linha:https://hdl.handle.net/2445/184474
Access Level:acceso abierto
Palavra-chave:Corea de Huntington
Mutació (Biologia)
Proteïna-tirosina-fosfatasa
Farmacogenètica
Inhibició
Huntington's chorea
Mutation (Biology)
Protein-tyrosine phosphatase
Pharmacogenetics
Inhibition
id ES_a6f68cceb6bc96725f5347e9bc2e54f6
oai_identifier_str oai:recercat.cat:2445/184474
network_acronym_str ES
network_name_str España
repository_id_str
spelling Pharmacogenetic Modulation of STEP improves motor and cognitive function in a mouse model of Huntington's disease.Garcia-Forn, MartaMartínez Torres, SaraGarcía-Díaz Barriga, GerardoAlberch i Vié, Jordi, 1959-Milà i Recasens, MontserratAzkona, GarikoitzPérez Navarro, EstherCorea de HuntingtonMutació (Biologia)Proteïna-tirosina-fosfatasaFarmacogenèticaInhibicióHuntington's choreaMutation (Biology)Protein-tyrosine phosphatasePharmacogeneticsInhibitionHuntington's disease (HD) is a hereditary neurodegenerative disorder caused by an expansion of a CAG repeat in the huntingtin (htt) gene, which results in an aberrant form of the protein (mhtt). This leads to motor and cognitive deficits associated with corticostriatal and hippocampal alterations. The levels of STriatal-Enriched protein tyrosine Phosphatase (STEP), a neural-specific tyrosine phosphatase that opposes the development of synaptic strengthening, are decreased in the striatum of HD patients and also in R6/1 mice, thereby contributing to the resistance to excitotoxicity described in this HD mouse model. Here, we aimed to analyze whether STEP inactivation plays a role in the pathophysiology of HD by investigating its effect on motor and cognitive impairment in the R6/1 mouse model of HD. We found that genetic deletion of STEP delayed the onset of motor dysfunction and prevented the appearance of cognitive deficits in R6/1 mice. This phenotype was accompanied by an increase in pERK1/2 levels, a delay in the decrease of striatal DARPP-32 levels and a reduction in the size of mhtt aggregates, both in the striatum and CA1 hippocampal region. We also found that acute pharmacological inhibition of STEP with TC-2153 improved cognitive function in R6/1 mice. In conclusion, our results show that deletion of STEP has a beneficial effect on motor coordination and cognition in a mouse model of HD suggesting that STEP inhibition could be a good therapeutic strategy in HD patients.Elsevier2022202220182022info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion10 p.application/pdfapplication/pdfhttps://hdl.handle.net/2445/184474Articles 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/10.1016/j.nbd.2018.08.024Neurobiology of Disease, 2018, vol. 120, p. 88-97https://doi.org/10.1016/j.nbd.2018.08.024cc-by-nc-nd (c) Elsevier, 2018https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1844742026-05-29T05:05:01Z
dc.title.none.fl_str_mv Pharmacogenetic Modulation of STEP improves motor and cognitive function in a mouse model of Huntington's disease.
title Pharmacogenetic Modulation of STEP improves motor and cognitive function in a mouse model of Huntington's disease.
spellingShingle Pharmacogenetic Modulation of STEP improves motor and cognitive function in a mouse model of Huntington's disease.
Garcia-Forn, Marta
Corea de Huntington
Mutació (Biologia)
Proteïna-tirosina-fosfatasa
Farmacogenètica
Inhibició
Huntington's chorea
Mutation (Biology)
Protein-tyrosine phosphatase
Pharmacogenetics
Inhibition
title_short Pharmacogenetic Modulation of STEP improves motor and cognitive function in a mouse model of Huntington's disease.
title_full Pharmacogenetic Modulation of STEP improves motor and cognitive function in a mouse model of Huntington's disease.
title_fullStr Pharmacogenetic Modulation of STEP improves motor and cognitive function in a mouse model of Huntington's disease.
title_full_unstemmed Pharmacogenetic Modulation of STEP improves motor and cognitive function in a mouse model of Huntington's disease.
title_sort Pharmacogenetic Modulation of STEP improves motor and cognitive function in a mouse model of Huntington's disease.
dc.creator.none.fl_str_mv Garcia-Forn, Marta
Martínez Torres, Sara
García-Díaz Barriga, Gerardo
Alberch i Vié, Jordi, 1959-
Milà i Recasens, Montserrat
Azkona, Garikoitz
Pérez Navarro, Esther
author Garcia-Forn, Marta
author_facet Garcia-Forn, Marta
Martínez Torres, Sara
García-Díaz Barriga, Gerardo
Alberch i Vié, Jordi, 1959-
Milà i Recasens, Montserrat
Azkona, Garikoitz
Pérez Navarro, Esther
author_role author
author2 Martínez Torres, Sara
García-Díaz Barriga, Gerardo
Alberch i Vié, Jordi, 1959-
Milà i Recasens, Montserrat
Azkona, Garikoitz
Pérez Navarro, Esther
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Corea de Huntington
Mutació (Biologia)
Proteïna-tirosina-fosfatasa
Farmacogenètica
Inhibició
Huntington's chorea
Mutation (Biology)
Protein-tyrosine phosphatase
Pharmacogenetics
Inhibition
topic Corea de Huntington
Mutació (Biologia)
Proteïna-tirosina-fosfatasa
Farmacogenètica
Inhibició
Huntington's chorea
Mutation (Biology)
Protein-tyrosine phosphatase
Pharmacogenetics
Inhibition
description Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an expansion of a CAG repeat in the huntingtin (htt) gene, which results in an aberrant form of the protein (mhtt). This leads to motor and cognitive deficits associated with corticostriatal and hippocampal alterations. The levels of STriatal-Enriched protein tyrosine Phosphatase (STEP), a neural-specific tyrosine phosphatase that opposes the development of synaptic strengthening, are decreased in the striatum of HD patients and also in R6/1 mice, thereby contributing to the resistance to excitotoxicity described in this HD mouse model. Here, we aimed to analyze whether STEP inactivation plays a role in the pathophysiology of HD by investigating its effect on motor and cognitive impairment in the R6/1 mouse model of HD. We found that genetic deletion of STEP delayed the onset of motor dysfunction and prevented the appearance of cognitive deficits in R6/1 mice. This phenotype was accompanied by an increase in pERK1/2 levels, a delay in the decrease of striatal DARPP-32 levels and a reduction in the size of mhtt aggregates, both in the striatum and CA1 hippocampal region. We also found that acute pharmacological inhibition of STEP with TC-2153 improved cognitive function in R6/1 mice. In conclusion, our results show that deletion of STEP has a beneficial effect on motor coordination and cognition in a mouse model of HD suggesting that STEP inhibition could be a good therapeutic strategy in HD patients.
publishDate 2018
dc.date.none.fl_str_mv 2018
2022
2022
2022
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/2445/184474
url https://hdl.handle.net/2445/184474
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/10.1016/j.nbd.2018.08.024
Neurobiology of Disease, 2018, vol. 120, p. 88-97
https://doi.org/10.1016/j.nbd.2018.08.024
dc.rights.none.fl_str_mv cc-by-nc-nd (c) Elsevier, 2018
https://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-nd (c) Elsevier, 2018
https://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 10 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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_ 1869415739594637312
score 15,812429

Registos relacionados