Cargando…
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...
Autores principales: | , , , , , , , |
---|---|
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 |
_version_ | 1783722813175103488 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8281260 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Society for Neuroscience |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT bordonemelinap fynknockdownpreventslevodopainduceddyskinesiainamousemodelofparkinsonsdisease AT damianichana fynknockdownpreventslevodopainduceddyskinesiainamousemodelofparkinsonsdisease AT bernardialejandra fynknockdownpreventslevodopainduceddyskinesiainamousemodelofparkinsonsdisease AT eidelmantomas fynknockdownpreventslevodopainduceddyskinesiainamousemodelofparkinsonsdisease AT sanzblascosara fynknockdownpreventslevodopainduceddyskinesiainamousemodelofparkinsonsdisease AT gershanikoscars fynknockdownpreventslevodopainduceddyskinesiainamousemodelofparkinsonsdisease AT avalemelena fynknockdownpreventslevodopainduceddyskinesiainamousemodelofparkinsonsdisease AT ferrariojuane fynknockdownpreventslevodopainduceddyskinesiainamousemodelofparkinsonsdisease |