Fyn knock-down prevents levodopa-induced dyskinesia in a mouse model of parkinson’s disease

Autores
Bordone, Melina Paula; Damianich, Ana; Bernardi, Maria Alejandra; Eidelman, Tomas; Sanz Blasco, Sara Isabel; Gershanik, Oscar Samuel; Avale, Maria Elena; Ferrario, Juan Esteban
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Dopamine replacement by levodopa (L-DOPA) is the most widely used therapy for Parkinson’s disease (PD), however patients often develop side effects, known as L-DOPA-induced dyskinesia (LID), that usually need therapeutic intervention. There are no suitable therapeutic options for LID, except for the use of the NMDA receptor (NMDA-R) antagonist amantadine, which has limited efficacy. The NMDA-R is indeed the most plausible target to manage LID in PD and recently the kinase Fyn, one of its key regulators, became a new putative molecular target involved in LID. The aim of this work was to reduce Fyn expression to alleviate LID in a mouse model of PD. We performed intrastriatal delivery of a designed micro-RNA against Fyn (miRNA-Fyn) in 6-OHDA-lesioned mice treated with L-DOPA. The miRNA-Fyn was delivered either before or after L-DOPA exposure to assess its ability to prevent or revert dyskinesia. Preadministration of miRNA-Fyn reduced LID with a concomitant reduction of FosB-DFosB protein levels, a marker of LID, as well as decreased phosphorylation of the NR2B-NMDA subunit, which is a main target of Fyn. On the other hand, post-L-DOPA delivery of miRNA-Fyn was less effective to revert already established dyskinesia, suggest-ing that early blocking of Fyn activity might be a more efficient therapeutic approach. Together, our results provide proof of concept about Fyn as a plausible therapeutic target to manage LID, and validate RNA si-lencing as a potential approach to locally reduce striatal Fyn, rising new perspectives for RNA therapy interventions in PD.
Fil: Bordone, Melina Paula. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Damianich, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Bernardi, Maria Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Eidelman, Tomas. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Sanz Blasco, Sara Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Gershanik, Oscar Samuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Avale, Maria Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Ferrario, Juan Esteban. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
FYN
LEVODOPA-INDUCED DYSKINESIAS
MICRORNA
NMDA
PARKINSON’S DISEASE
RNA THERAPY
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/153197
Acceder
id CONICETDig_cb8ae110573ce126da85a10c996c2790
oai_identifier_str oai:ri.conicet.gov.ar:11336/153197
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Fyn knock-down prevents levodopa-induced dyskinesia in a mouse model of parkinson’s diseaseBordone, Melina PaulaDamianich, AnaBernardi, Maria AlejandraEidelman, TomasSanz Blasco, Sara IsabelGershanik, Oscar SamuelAvale, Maria ElenaFerrario, Juan EstebanFYNLEVODOPA-INDUCED DYSKINESIASMICRORNANMDAPARKINSON’S DISEASERNA THERAPYhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Dopamine replacement by levodopa (L-DOPA) is the most widely used therapy for Parkinson’s disease (PD), however patients often develop side effects, known as L-DOPA-induced dyskinesia (LID), that usually need therapeutic intervention. There are no suitable therapeutic options for LID, except for the use of the NMDA receptor (NMDA-R) antagonist amantadine, which has limited efficacy. The NMDA-R is indeed the most plausible target to manage LID in PD and recently the kinase Fyn, one of its key regulators, became a new putative molecular target involved in LID. The aim of this work was to reduce Fyn expression to alleviate LID in a mouse model of PD. We performed intrastriatal delivery of a designed micro-RNA against Fyn (miRNA-Fyn) in 6-OHDA-lesioned mice treated with L-DOPA. The miRNA-Fyn was delivered either before or after L-DOPA exposure to assess its ability to prevent or revert dyskinesia. Preadministration of miRNA-Fyn reduced LID with a concomitant reduction of FosB-DFosB protein levels, a marker of LID, as well as decreased phosphorylation of the NR2B-NMDA subunit, which is a main target of Fyn. On the other hand, post-L-DOPA delivery of miRNA-Fyn was less effective to revert already established dyskinesia, suggest-ing that early blocking of Fyn activity might be a more efficient therapeutic approach. Together, our results provide proof of concept about Fyn as a plausible therapeutic target to manage LID, and validate RNA si-lencing as a potential approach to locally reduce striatal Fyn, rising new perspectives for RNA therapy interventions in PD.Fil: Bordone, Melina Paula. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Damianich, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Bernardi, Maria Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Eidelman, Tomas. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sanz Blasco, Sara Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Gershanik, Oscar Samuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Avale, Maria Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Ferrario, Juan Esteban. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaSociety for Neuroscience2021-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/153197Bordone, Melina Paula; Damianich, Ana; Bernardi, Maria Alejandra; Eidelman, Tomas; Sanz Blasco, Sara Isabel; et al.; Fyn knock-down prevents levodopa-induced dyskinesia in a mouse model of parkinson’s disease; Society for Neuroscience; eNeuro; 8; 4; 7-2021; 1-162373-2822CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1523/ENEURO.0559-20.2021info:eu-repo/semantics/altIdentifier/url/https://www.eneuro.org/content/8/4/ENEURO.0559-20.2021info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:22:48Zoai:ri.conicet.gov.ar:11336/153197instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:22:49.061CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Fyn knock-down prevents levodopa-induced dyskinesia in a mouse model of parkinson’s disease
title Fyn knock-down prevents levodopa-induced dyskinesia in a mouse model of parkinson’s disease
spellingShingle Fyn knock-down prevents levodopa-induced dyskinesia in a mouse model of parkinson’s disease
Bordone, Melina Paula
FYN
LEVODOPA-INDUCED DYSKINESIAS
MICRORNA
NMDA
PARKINSON’S DISEASE
RNA THERAPY
title_short Fyn knock-down prevents levodopa-induced dyskinesia in a mouse model of parkinson’s disease
title_full Fyn knock-down prevents levodopa-induced dyskinesia in a mouse model of parkinson’s disease
title_fullStr Fyn knock-down prevents levodopa-induced dyskinesia in a mouse model of parkinson’s disease
title_full_unstemmed Fyn knock-down prevents levodopa-induced dyskinesia in a mouse model of parkinson’s disease
title_sort Fyn knock-down prevents levodopa-induced dyskinesia in a mouse model of parkinson’s disease
dc.creator.none.fl_str_mv Bordone, Melina Paula
Damianich, Ana
Bernardi, Maria Alejandra
Eidelman, Tomas
Sanz Blasco, Sara Isabel
Gershanik, Oscar Samuel
Avale, Maria Elena
Ferrario, Juan Esteban
author Bordone, Melina Paula
author_facet Bordone, Melina Paula
Damianich, Ana
Bernardi, Maria Alejandra
Eidelman, Tomas
Sanz Blasco, Sara Isabel
Gershanik, Oscar Samuel
Avale, Maria Elena
Ferrario, Juan Esteban
author_role author
author2 Damianich, Ana
Bernardi, Maria Alejandra
Eidelman, Tomas
Sanz Blasco, Sara Isabel
Gershanik, Oscar Samuel
Avale, Maria Elena
Ferrario, Juan Esteban
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv FYN
LEVODOPA-INDUCED DYSKINESIAS
MICRORNA
NMDA
PARKINSON’S DISEASE
RNA THERAPY
topic FYN
LEVODOPA-INDUCED DYSKINESIAS
MICRORNA
NMDA
PARKINSON’S DISEASE
RNA THERAPY
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Dopamine replacement by levodopa (L-DOPA) is the most widely used therapy for Parkinson’s disease (PD), however patients often develop side effects, known as L-DOPA-induced dyskinesia (LID), that usually need therapeutic intervention. There are no suitable therapeutic options for LID, except for the use of the NMDA receptor (NMDA-R) antagonist amantadine, which has limited efficacy. The NMDA-R is indeed the most plausible target to manage LID in PD and recently the kinase Fyn, one of its key regulators, became a new putative molecular target involved in LID. The aim of this work was to reduce Fyn expression to alleviate LID in a mouse model of PD. We performed intrastriatal delivery of a designed micro-RNA against Fyn (miRNA-Fyn) in 6-OHDA-lesioned mice treated with L-DOPA. The miRNA-Fyn was delivered either before or after L-DOPA exposure to assess its ability to prevent or revert dyskinesia. Preadministration of miRNA-Fyn reduced LID with a concomitant reduction of FosB-DFosB protein levels, a marker of LID, as well as decreased phosphorylation of the NR2B-NMDA subunit, which is a main target of Fyn. On the other hand, post-L-DOPA delivery of miRNA-Fyn was less effective to revert already established dyskinesia, suggest-ing that early blocking of Fyn activity might be a more efficient therapeutic approach. Together, our results provide proof of concept about Fyn as a plausible therapeutic target to manage LID, and validate RNA si-lencing as a potential approach to locally reduce striatal Fyn, rising new perspectives for RNA therapy interventions in PD.
Fil: Bordone, Melina Paula. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Damianich, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Bernardi, Maria Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Eidelman, Tomas. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Sanz Blasco, Sara Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Gershanik, Oscar Samuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Avale, Maria Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Ferrario, Juan Esteban. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description Dopamine replacement by levodopa (L-DOPA) is the most widely used therapy for Parkinson’s disease (PD), however patients often develop side effects, known as L-DOPA-induced dyskinesia (LID), that usually need therapeutic intervention. There are no suitable therapeutic options for LID, except for the use of the NMDA receptor (NMDA-R) antagonist amantadine, which has limited efficacy. The NMDA-R is indeed the most plausible target to manage LID in PD and recently the kinase Fyn, one of its key regulators, became a new putative molecular target involved in LID. The aim of this work was to reduce Fyn expression to alleviate LID in a mouse model of PD. We performed intrastriatal delivery of a designed micro-RNA against Fyn (miRNA-Fyn) in 6-OHDA-lesioned mice treated with L-DOPA. The miRNA-Fyn was delivered either before or after L-DOPA exposure to assess its ability to prevent or revert dyskinesia. Preadministration of miRNA-Fyn reduced LID with a concomitant reduction of FosB-DFosB protein levels, a marker of LID, as well as decreased phosphorylation of the NR2B-NMDA subunit, which is a main target of Fyn. On the other hand, post-L-DOPA delivery of miRNA-Fyn was less effective to revert already established dyskinesia, suggest-ing that early blocking of Fyn activity might be a more efficient therapeutic approach. Together, our results provide proof of concept about Fyn as a plausible therapeutic target to manage LID, and validate RNA si-lencing as a potential approach to locally reduce striatal Fyn, rising new perspectives for RNA therapy interventions in PD.
publishDate 2021
dc.date.none.fl_str_mv 2021-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/153197
Bordone, Melina Paula; Damianich, Ana; Bernardi, Maria Alejandra; Eidelman, Tomas; Sanz Blasco, Sara Isabel; et al.; Fyn knock-down prevents levodopa-induced dyskinesia in a mouse model of parkinson’s disease; Society for Neuroscience; eNeuro; 8; 4; 7-2021; 1-16
2373-2822
CONICET Digital
CONICET
url http://hdl.handle.net/11336/153197
identifier_str_mv Bordone, Melina Paula; Damianich, Ana; Bernardi, Maria Alejandra; Eidelman, Tomas; Sanz Blasco, Sara Isabel; et al.; Fyn knock-down prevents levodopa-induced dyskinesia in a mouse model of parkinson’s disease; Society for Neuroscience; eNeuro; 8; 4; 7-2021; 1-16
2373-2822
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1523/ENEURO.0559-20.2021
info:eu-repo/semantics/altIdentifier/url/https://www.eneuro.org/content/8/4/ENEURO.0559-20.2021
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Society for Neuroscience
publisher.none.fl_str_mv Society for Neuroscience
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1844614221037305856
score 13.070432

Publicaciones similares