Synaptic RTP801 contributes to motor-learning dysfunction in Huntington's disease

RTP801/REDD1 is a stress-responsive protein that mediates mutant huntingtin (mhtt) toxicity in cellular models and is up regulated in Huntington's disease (HD) patients' putamen. Here, we investigated whether RTP801 is involved in motor impairment in HD by affecting striatal synaptic plast...

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Autores: Martín Flores, Núria, Pérez Sisqués, Leticia, Creus Muncunill, Jordi, Masana Nadal, Mercè, Ginés Padrós, Silvia, Alberch i Vié, Jordi, 1959-, Pérez Navarro, Esther, Malagelada Grau, Cristina
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
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:2445/183148
Acceso en línea:https://hdl.handle.net/2445/183148
Access Level:acceso abierto
Palabra clave:Corea de Huntington
Neuroplasticitat
Huntington's chorea
Neuroplasticity
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spelling Synaptic RTP801 contributes to motor-learning dysfunction in Huntington's diseaseMartín Flores, NúriaPérez Sisqués, LeticiaCreus Muncunill, JordiMasana Nadal, MercèGinés Padrós, SilviaAlberch i Vié, Jordi, 1959-Pérez Navarro, EstherMalagelada Grau, CristinaCorea de HuntingtonNeuroplasticitatHuntington's choreaNeuroplasticityRTP801/REDD1 is a stress-responsive protein that mediates mutant huntingtin (mhtt) toxicity in cellular models and is up regulated in Huntington's disease (HD) patients' putamen. Here, we investigated whether RTP801 is involved in motor impairment in HD by affecting striatal synaptic plasticity. To explore this hypothesis, ectopic mhtt was over expressed in cultured rat primary neurons. Moreover, the protein levels of RTP801 were assessed in homogenates and crude synaptic fractions from human postmortem HD brains and mouse models of HD. Finally, striatal RTP801 expression was knocked down with adeno-associated viral particles containing a shRNA in the R6/1 mouse model of HD and motor learning was then tested. Ectopic mhtt elevated RTP801 in synapses of cultured neurons. RTP801 was also up regulated in striatal synapses from HD patients and mouse models. Knocking down RTP801 in the R6/1 mouse striatum prevented motor-learning impairment. RTP801 silencing normalized the Ser473 Akt hyperphosphorylation by downregulating Rictor and it induced synaptic elevation of calcium permeable GluA1 subunit and TrkB receptor levels, suggesting an enhancement in synaptic plasticity. These results indicate that mhtt-induced RTP801 mediates motor dysfunction in a HD murine model, revealing a potential role in the human disease. These findings open a new therapeutic framework focused on the RTP801/Akt/mTOR axis.Nature Publishing Group2022202220202022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion15 p.application/pdfapplication/pdfhttps://hdl.handle.net/2445/183148Articles 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)InglésReproducció del document publicat a: https://doi.org/10.1038/s41419-020-02775-5Cell Death and Disease, 2020, vol. 11, num. 569https://doi.org/10.1038/s41419-020-02775-5cc-by-nc-sa (c) Martín Flores, Núria et al., 2020https://creativecommons.org/licenses/by-nc-sa/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1831482026-05-29T05:05:01Z
dc.title.none.fl_str_mv Synaptic RTP801 contributes to motor-learning dysfunction in Huntington's disease
title Synaptic RTP801 contributes to motor-learning dysfunction in Huntington's disease
spellingShingle Synaptic RTP801 contributes to motor-learning dysfunction in Huntington's disease
Martín Flores, Núria
Corea de Huntington
Neuroplasticitat
Huntington's chorea
Neuroplasticity
title_short Synaptic RTP801 contributes to motor-learning dysfunction in Huntington's disease
title_full Synaptic RTP801 contributes to motor-learning dysfunction in Huntington's disease
title_fullStr Synaptic RTP801 contributes to motor-learning dysfunction in Huntington's disease
title_full_unstemmed Synaptic RTP801 contributes to motor-learning dysfunction in Huntington's disease
title_sort Synaptic RTP801 contributes to motor-learning dysfunction in Huntington's disease
dc.creator.none.fl_str_mv Martín Flores, Núria
Pérez Sisqués, Leticia
Creus Muncunill, Jordi
Masana Nadal, Mercè
Ginés Padrós, Silvia
Alberch i Vié, Jordi, 1959-
Pérez Navarro, Esther
Malagelada Grau, Cristina
author Martín Flores, Núria
author_facet Martín Flores, Núria
Pérez Sisqués, Leticia
Creus Muncunill, Jordi
Masana Nadal, Mercè
Ginés Padrós, Silvia
Alberch i Vié, Jordi, 1959-
Pérez Navarro, Esther
Malagelada Grau, Cristina
author_role author
author2 Pérez Sisqués, Leticia
Creus Muncunill, Jordi
Masana Nadal, Mercè
Ginés Padrós, Silvia
Alberch i Vié, Jordi, 1959-
Pérez Navarro, Esther
Malagelada Grau, Cristina
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Corea de Huntington
Neuroplasticitat
Huntington's chorea
Neuroplasticity
topic Corea de Huntington
Neuroplasticitat
Huntington's chorea
Neuroplasticity
description RTP801/REDD1 is a stress-responsive protein that mediates mutant huntingtin (mhtt) toxicity in cellular models and is up regulated in Huntington's disease (HD) patients' putamen. Here, we investigated whether RTP801 is involved in motor impairment in HD by affecting striatal synaptic plasticity. To explore this hypothesis, ectopic mhtt was over expressed in cultured rat primary neurons. Moreover, the protein levels of RTP801 were assessed in homogenates and crude synaptic fractions from human postmortem HD brains and mouse models of HD. Finally, striatal RTP801 expression was knocked down with adeno-associated viral particles containing a shRNA in the R6/1 mouse model of HD and motor learning was then tested. Ectopic mhtt elevated RTP801 in synapses of cultured neurons. RTP801 was also up regulated in striatal synapses from HD patients and mouse models. Knocking down RTP801 in the R6/1 mouse striatum prevented motor-learning impairment. RTP801 silencing normalized the Ser473 Akt hyperphosphorylation by downregulating Rictor and it induced synaptic elevation of calcium permeable GluA1 subunit and TrkB receptor levels, suggesting an enhancement in synaptic plasticity. These results indicate that mhtt-induced RTP801 mediates motor dysfunction in a HD murine model, revealing a potential role in the human disease. These findings open a new therapeutic framework focused on the RTP801/Akt/mTOR axis.
publishDate 2020
dc.date.none.fl_str_mv 2020
2022
2022
2022
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/2445/183148
url https://hdl.handle.net/2445/183148
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/10.1038/s41419-020-02775-5
Cell Death and Disease, 2020, vol. 11, num. 569
https://doi.org/10.1038/s41419-020-02775-5
dc.rights.none.fl_str_mv cc-by-nc-sa (c) Martín Flores, Núria et al., 2020
https://creativecommons.org/licenses/by-nc-sa/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-sa (c) Martín Flores, Núria et al., 2020
https://creativecommons.org/licenses/by-nc-sa/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 15 p.
application/pdf
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_ 1869417169263001600
score 15,81155

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