RNAi-Based GIuN3A Silencing Prevents and Reverses Disease Phenotypes Induced by Mutant huntingtin

Huntington’s disease (HD) is a dominantly inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. HD symptoms include severe motor, cognitive, and psychiatric impairments that result from dysfunction and later degeneration of medium-sized spiny neu...

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Autores: Marco-Martínez, S. (Sonia)|||/items/07a08866-003b-4423-9412-ec9bb8140553, Murillo, A. (Alvaro)|||/items/74925997-4c4a-4c72-bc99-3a41683fc8f9, Perez-Otaño, I. (Isabel)|||/items/7ae2e432-8829-4216-8ef8-6ec17b30d4e9
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglés
OAI Identifier:oai:dadun.unav.edu:10171/65449
Acceso en línea:https://hdl.handle.net/10171/65449
Access Level:acceso abierto
Palabra clave:Huntington’s disease (HD)
NMDA-type glutamate receptors
Polyglutamine tract
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spelling RNAi-Based GIuN3A Silencing Prevents and Reverses Disease Phenotypes Induced by Mutant huntingtinMarco-Martínez, S. (Sonia)|||/items/07a08866-003b-4423-9412-ec9bb8140553Murillo, A. (Alvaro)|||/items/74925997-4c4a-4c72-bc99-3a41683fc8f9Perez-Otaño, I. (Isabel)|||/items/7ae2e432-8829-4216-8ef8-6ec17b30d4e9Huntington’s disease (HD)NMDA-type glutamate receptorsPolyglutamine tractHuntington’s disease (HD) is a dominantly inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. HD symptoms include severe motor, cognitive, and psychiatric impairments that result from dysfunction and later degeneration of medium-sized spiny neurons (MSNs) in the striatum. A key early pathogenic mechanism is dysregulated synaptic transmission due to enhanced surface expression of juvenile NMDA-type glutamate receptors containing GluN3A subunits, which trigger the aberrant pruning of synapses formed by cortical afferents onto MSNs. Here, we tested the therapeutic potential of silencing GluN3A expression in YAC128 mice, a well-established HD model. Recombinant adeno-associated viruses encoding a short-hairpin RNA against GluN3A (rAAV-shGluN3A) were generated, and the ability of different serotypes to transduce MSNs was compared. A single injection of rAAV9-shGluN3A into the striatum of 1-month-old mice drove potent (>90%) and long-lasting reductions of GluN3A expression in MSNs, prevented dendritic spine loss and improved motor performance in YAC128 mice. Later delivery, when spine pathology is already apparent, was also effective. Our data provide proof-of-concept for GluN3A silencing as a beneficial strategy to prevent or reverse corticostriatal disconnectivity and motor impairment in HD and support the use of RNAi-based or small-molecule approaches for harnessing this therapeutic potential.Cell PressDadun. Depósito Académico Digital Universidad de Navarra20232023-02-1420182018-01-0120182018-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/65449reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/654492026-06-21T12:47:57Z
dc.title.none.fl_str_mv RNAi-Based GIuN3A Silencing Prevents and Reverses Disease Phenotypes Induced by Mutant huntingtin
title RNAi-Based GIuN3A Silencing Prevents and Reverses Disease Phenotypes Induced by Mutant huntingtin
spellingShingle RNAi-Based GIuN3A Silencing Prevents and Reverses Disease Phenotypes Induced by Mutant huntingtin
Marco-Martínez, S. (Sonia)|||/items/07a08866-003b-4423-9412-ec9bb8140553
Huntington’s disease (HD)
NMDA-type glutamate receptors
Polyglutamine tract
title_short RNAi-Based GIuN3A Silencing Prevents and Reverses Disease Phenotypes Induced by Mutant huntingtin
title_full RNAi-Based GIuN3A Silencing Prevents and Reverses Disease Phenotypes Induced by Mutant huntingtin
title_fullStr RNAi-Based GIuN3A Silencing Prevents and Reverses Disease Phenotypes Induced by Mutant huntingtin
title_full_unstemmed RNAi-Based GIuN3A Silencing Prevents and Reverses Disease Phenotypes Induced by Mutant huntingtin
title_sort RNAi-Based GIuN3A Silencing Prevents and Reverses Disease Phenotypes Induced by Mutant huntingtin
dc.creator.none.fl_str_mv Marco-Martínez, S. (Sonia)|||/items/07a08866-003b-4423-9412-ec9bb8140553
Murillo, A. (Alvaro)|||/items/74925997-4c4a-4c72-bc99-3a41683fc8f9
Perez-Otaño, I. (Isabel)|||/items/7ae2e432-8829-4216-8ef8-6ec17b30d4e9
author Marco-Martínez, S. (Sonia)|||/items/07a08866-003b-4423-9412-ec9bb8140553
author_facet Marco-Martínez, S. (Sonia)|||/items/07a08866-003b-4423-9412-ec9bb8140553
Murillo, A. (Alvaro)|||/items/74925997-4c4a-4c72-bc99-3a41683fc8f9
Perez-Otaño, I. (Isabel)|||/items/7ae2e432-8829-4216-8ef8-6ec17b30d4e9
author_role author
author2 Murillo, A. (Alvaro)|||/items/74925997-4c4a-4c72-bc99-3a41683fc8f9
Perez-Otaño, I. (Isabel)|||/items/7ae2e432-8829-4216-8ef8-6ec17b30d4e9
author2_role author
author
dc.contributor.none.fl_str_mv Dadun. Depósito Académico Digital Universidad de Navarra
dc.subject.none.fl_str_mv Huntington’s disease (HD)
NMDA-type glutamate receptors
Polyglutamine tract
topic Huntington’s disease (HD)
NMDA-type glutamate receptors
Polyglutamine tract
description Huntington’s disease (HD) is a dominantly inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. HD symptoms include severe motor, cognitive, and psychiatric impairments that result from dysfunction and later degeneration of medium-sized spiny neurons (MSNs) in the striatum. A key early pathogenic mechanism is dysregulated synaptic transmission due to enhanced surface expression of juvenile NMDA-type glutamate receptors containing GluN3A subunits, which trigger the aberrant pruning of synapses formed by cortical afferents onto MSNs. Here, we tested the therapeutic potential of silencing GluN3A expression in YAC128 mice, a well-established HD model. Recombinant adeno-associated viruses encoding a short-hairpin RNA against GluN3A (rAAV-shGluN3A) were generated, and the ability of different serotypes to transduce MSNs was compared. A single injection of rAAV9-shGluN3A into the striatum of 1-month-old mice drove potent (>90%) and long-lasting reductions of GluN3A expression in MSNs, prevented dendritic spine loss and improved motor performance in YAC128 mice. Later delivery, when spine pathology is already apparent, was also effective. Our data provide proof-of-concept for GluN3A silencing as a beneficial strategy to prevent or reverse corticostriatal disconnectivity and motor impairment in HD and support the use of RNAi-based or small-molecule approaches for harnessing this therapeutic potential.
publishDate 2018
dc.date.none.fl_str_mv 2018
2018-01-01
2018
2018-01-01
2023
2023-02-14
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/10171/65449
url https://hdl.handle.net/10171/65449
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Cell Press
publisher.none.fl_str_mv Cell Press
dc.source.none.fl_str_mv reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra
instname:Universidad de Navarra
instname_str Universidad de Navarra
reponame_str Dadun. Depósito Académico Digital de la Universidad de Navarra
collection Dadun. Depósito Académico Digital de la Universidad de Navarra
repository.name.fl_str_mv
repository.mail.fl_str_mv
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