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Fyn Knock-Down Prevents Levodopa-Induced Dyskinesia in a Mouse Model of Parkinson’s Disease

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...

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Autores principales: Bordone, Melina P., Damianich, Ana, Bernardi, Alejandra, Eidelman, Tomas, Sanz-Blasco, Sara, Gershanik, Oscar S., Avale, M. Elena, Ferrario, Juan E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for Neuroscience 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281260/
https://www.ncbi.nlm.nih.gov/pubmed/34099487
http://dx.doi.org/10.1523/ENEURO.0559-20.2021
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author Bordone, Melina P.
Damianich, Ana
Bernardi, Alejandra
Eidelman, Tomas
Sanz-Blasco, Sara
Gershanik, Oscar S.
Avale, M. Elena
Ferrario, Juan E.
author_facet Bordone, Melina P.
Damianich, Ana
Bernardi, Alejandra
Eidelman, Tomas
Sanz-Blasco, Sara
Gershanik, Oscar S.
Avale, M. Elena
Ferrario, Juan E.
author_sort Bordone, Melina P.
collection PubMed
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-ΔFosB 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, suggesting 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 silencing as a potential approach to locally reduce striatal Fyn, rising new perspectives for RNA therapy interventions in PD.
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spelling pubmed-82812602021-07-16 Fyn Knock-Down Prevents Levodopa-Induced Dyskinesia in a Mouse Model of Parkinson’s Disease Bordone, Melina P. Damianich, Ana Bernardi, Alejandra Eidelman, Tomas Sanz-Blasco, Sara Gershanik, Oscar S. Avale, M. Elena Ferrario, Juan E. eNeuro Research Article: New Research 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-ΔFosB 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, suggesting 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 silencing as a potential approach to locally reduce striatal Fyn, rising new perspectives for RNA therapy interventions in PD. Society for Neuroscience 2021-07-12 /pmc/articles/PMC8281260/ /pubmed/34099487 http://dx.doi.org/10.1523/ENEURO.0559-20.2021 Text en Copyright © 2021 Bordone et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article: New Research
Bordone, Melina P.
Damianich, Ana
Bernardi, Alejandra
Eidelman, Tomas
Sanz-Blasco, Sara
Gershanik, Oscar S.
Avale, M. Elena
Ferrario, Juan E.
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
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_short 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
topic Research Article: New Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281260/
https://www.ncbi.nlm.nih.gov/pubmed/34099487
http://dx.doi.org/10.1523/ENEURO.0559-20.2021
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