Rabphilin 3A: A novel target for the treatment of levodopa-induced dyskinesias.
Neurobiology of Disease. 2017-12-01; 108: 54-64
DOI: 10.1016/j.nbd.2017.08.001
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Stanic J(1), Mellone M(2), Napolitano F(3), Racca C(4), Zianni E(1), Minocci D(1), Ghiglieri V(5), Thiolat ML(6), Li Q(7), Longhi A(1), De Rosa A(8), Picconi B(9), Bezard E(10), Calabresi P(11), Di Luca M(1), Usiello A(12), Gardoni F(13).
Author information:
(1)DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133, Milano, Italy.
(2)DiSFeB, 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, Italy.
(3)Ceinge Biotecnologie Avanzate, Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples « Federico II », Naples, Italy.
(4)Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
(5)Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, 00143 Roma, Italy; Department of Philosophy, Human, Social and Educational Sciences, University of Perugia, Perugia, Italy.
(6)Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
(7)Motac Neuroscience Ltd, Manchester, United Kingdom; Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, China.
(8)Ceinge Biotecnologie Avanzate, Naples, Italy.
(9)Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, 00143 Roma, Italy.
(10)Univ. 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, China.
(11)Laboratorio 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, Italy.
(12)Ceinge Biotecnologie Avanzate, Naples, Italy; Department of Environmental,
Biological and Pharmaceutical Sciences and Technologies, University of Campania,
Luigi Vanvitelli, Caserta, Italy.
(13)DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università
degli Studi di Milano, 20133, Milano, Italy. Electronic address:
.
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.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.