Rabphilin 3A: A novel target for the treatment of levodopa-induced dyskinesias
N-methyl-d-aspartate receptor (NMDAR) subunit composition strictly commands receptor function and pharmacological responses. Changes in NMDAR subunit composition have been documented in brain disorders such as Parkinson's disease (PD) and levodopa (L-DOPA)-induced dyskinesias (LIDs), where an i...
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Format: | Article |
Language: | English |
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Elsevier
2017-12-01
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Series: | Neurobiology of Disease |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S096999611730181X |
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doaj-d2e15428dadb42fc83209c5ddb2f8c6e |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jennifer Stanic Manuela Mellone Francesco Napolitano Claudia Racca Elisa Zianni Daiana Minocci Veronica Ghiglieri Marie-Laure Thiolat Qin Li Annalisa Longhi Arianna De Rosa Barbara Picconi Erwan Bezard Paolo Calabresi Monica Di Luca Alessandro Usiello Fabrizio Gardoni |
spellingShingle |
Jennifer Stanic Manuela Mellone Francesco Napolitano Claudia Racca Elisa Zianni Daiana Minocci Veronica Ghiglieri Marie-Laure Thiolat Qin Li Annalisa Longhi Arianna De Rosa Barbara Picconi Erwan Bezard Paolo Calabresi Monica Di Luca Alessandro Usiello Fabrizio Gardoni Rabphilin 3A: A novel target for the treatment of levodopa-induced dyskinesias Neurobiology of Disease N-methyl-d-aspartate receptor Levodopa-induced dyskinesias Pharmacological target Cell-permeable peptides |
author_facet |
Jennifer Stanic Manuela Mellone Francesco Napolitano Claudia Racca Elisa Zianni Daiana Minocci Veronica Ghiglieri Marie-Laure Thiolat Qin Li Annalisa Longhi Arianna De Rosa Barbara Picconi Erwan Bezard Paolo Calabresi Monica Di Luca Alessandro Usiello Fabrizio Gardoni |
author_sort |
Jennifer Stanic |
title |
Rabphilin 3A: A novel target for the treatment of levodopa-induced dyskinesias |
title_short |
Rabphilin 3A: A novel target for the treatment of levodopa-induced dyskinesias |
title_full |
Rabphilin 3A: A novel target for the treatment of levodopa-induced dyskinesias |
title_fullStr |
Rabphilin 3A: A novel target for the treatment of levodopa-induced dyskinesias |
title_full_unstemmed |
Rabphilin 3A: A novel target for the treatment of levodopa-induced dyskinesias |
title_sort |
rabphilin 3a: a novel target for the treatment of levodopa-induced dyskinesias |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2017-12-01 |
description |
N-methyl-d-aspartate receptor (NMDAR) subunit composition strictly commands receptor function and pharmacological responses. Changes in NMDAR subunit composition have been documented in brain disorders such as Parkinson's disease (PD) and levodopa (L-DOPA)-induced dyskinesias (LIDs), where an increase of NMDAR GluN2A/GluN2B subunit ratio at striatal synapses has been observed. A therapeutic approach aimed at rebalancing NMDAR synaptic composition represents a valuable strategy for PD and LIDs. To this, the comprehension of the molecular mechanisms regulating the synaptic localization of different NMDAR subtypes is required.We have recently demonstrated that Rabphilin 3A (Rph3A) is a new binding partner of NMDARs containing the GluN2A subunit and that it plays a crucial function in the synaptic stabilization of these receptors. Considering that protein-protein interactions govern the synaptic retention of NMDARs, the purpose of this work was to analyse the role of Rph3A and Rph3A/NMDAR complex in PD and LIDs, and to modulate Rph3A/GluN2A interaction to counteract the aberrant motor behaviour associated to chronic L-DOPA administration. Thus, an array of biochemical, immunohistochemical and pharmacological tools together with electron microscopy were applied in this study. Here we found that Rph3A is localized at the striatal postsynaptic density where it interacts with GluN2A. Notably, Rph3A expression at the synapse and its interaction with GluN2A-containing NMDARs were increased in parkinsonian rats displaying a dyskinetic profile. Acute treatment of dyskinetic animals with a cell-permeable peptide able to interfere with Rph3A/GluN2A binding significantly reduced their abnormal motor behaviour.Altogether, our findings indicate that Rph3A activity is linked to the aberrant synaptic localization of GluN2A-expressing NMDARs characterizing LIDs. Thus, we suggest that Rph3A/GluN2A complex could represent an innovative therapeutic target for those pathological conditions where NMDAR composition is significantly altered. |
topic |
N-methyl-d-aspartate receptor Levodopa-induced dyskinesias Pharmacological target Cell-permeable peptides |
url |
http://www.sciencedirect.com/science/article/pii/S096999611730181X |
work_keys_str_mv |
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doaj-d2e15428dadb42fc83209c5ddb2f8c6e2021-03-22T12:45:45ZengElsevierNeurobiology of Disease1095-953X2017-12-011085464Rabphilin 3A: A novel target for the treatment of levodopa-induced dyskinesiasJennifer Stanic0Manuela Mellone1Francesco Napolitano2Claudia Racca3Elisa Zianni4Daiana Minocci5Veronica Ghiglieri6Marie-Laure Thiolat7Qin Li8Annalisa Longhi9Arianna De Rosa10Barbara Picconi11Erwan Bezard12Paolo Calabresi13Monica Di Luca14Alessandro Usiello15Fabrizio Gardoni16DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133, Milano, ItalyDiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133, Milano, Italy; Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, Luigi Vanvitelli, Caserta, ItalyCeinge Biotecnologie Avanzate, Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples ''Federico II'', Naples, ItalyInstitute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UKDiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133, Milano, ItalyDiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133, Milano, ItalyLaboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, 00143 Roma, Italy; Department of Philosophy, Human, Social and Educational Sciences, University of Perugia, Perugia, ItalyUniv. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, FranceMotac Neuroscience Ltd, Manchester, United Kingdom; Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, ChinaDiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133, Milano, ItalyCeinge Biotecnologie Avanzate, Naples, ItalyLaboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, 00143 Roma, ItalyUniv. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; Motac Neuroscience Ltd, Manchester, United Kingdom; Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, ChinaLaboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, 00143 Roma, Italy; Clinica Neurologica, Università degli studi di Perugia, Ospedale Santa Maria della Misericordia, S. Andrea delle Fratte, 06156 Perugia, ItalyDiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133, Milano, ItalyCeinge Biotecnologie Avanzate, Naples, Italy; Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, Luigi Vanvitelli, Caserta, ItalyDiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133, Milano, Italy; Corresponding author at: Dept. Pharmacological and Biomolecular Sciences, University of Milano, Via Balzaretti 9, 20133 Milano, Italy.N-methyl-d-aspartate receptor (NMDAR) subunit composition strictly commands receptor function and pharmacological responses. Changes in NMDAR subunit composition have been documented in brain disorders such as Parkinson's disease (PD) and levodopa (L-DOPA)-induced dyskinesias (LIDs), where an increase of NMDAR GluN2A/GluN2B subunit ratio at striatal synapses has been observed. A therapeutic approach aimed at rebalancing NMDAR synaptic composition represents a valuable strategy for PD and LIDs. To this, the comprehension of the molecular mechanisms regulating the synaptic localization of different NMDAR subtypes is required.We have recently demonstrated that Rabphilin 3A (Rph3A) is a new binding partner of NMDARs containing the GluN2A subunit and that it plays a crucial function in the synaptic stabilization of these receptors. Considering that protein-protein interactions govern the synaptic retention of NMDARs, the purpose of this work was to analyse the role of Rph3A and Rph3A/NMDAR complex in PD and LIDs, and to modulate Rph3A/GluN2A interaction to counteract the aberrant motor behaviour associated to chronic L-DOPA administration. Thus, an array of biochemical, immunohistochemical and pharmacological tools together with electron microscopy were applied in this study. Here we found that Rph3A is localized at the striatal postsynaptic density where it interacts with GluN2A. Notably, Rph3A expression at the synapse and its interaction with GluN2A-containing NMDARs were increased in parkinsonian rats displaying a dyskinetic profile. Acute treatment of dyskinetic animals with a cell-permeable peptide able to interfere with Rph3A/GluN2A binding significantly reduced their abnormal motor behaviour.Altogether, our findings indicate that Rph3A activity is linked to the aberrant synaptic localization of GluN2A-expressing NMDARs characterizing LIDs. Thus, we suggest that Rph3A/GluN2A complex could represent an innovative therapeutic target for those pathological conditions where NMDAR composition is significantly altered.http://www.sciencedirect.com/science/article/pii/S096999611730181XN-methyl-d-aspartate receptorLevodopa-induced dyskinesiasPharmacological targetCell-permeable peptides |