PSD-95 expression controls l-DOPA dyskinesia through dopamine D1 receptor trafficking
Gregory Porras, Amandine Berthet, Benjamin Dehay, Qin Li, Laurent Ladepeche, Elisabeth Normand, Sandra Dovero, Audrey Martinez, Evelyne Doudnikoff, Marie-Laure Martin-Négrier, Qin Chuan, Bertrand Bloch, Daniel Choquet, Eric Boué-Grabot, Laurent Groc, Erwan Bezard
Gregory Porras, Amandine Berthet, Benjamin Dehay, Qin Li, Laurent Ladepeche, Elisabeth Normand, Sandra Dovero, Audrey Martinez, Evelyne Doudnikoff, Marie-Laure Martin-Négrier, Qin Chuan, Bertrand Bloch, Daniel Choquet, Eric Boué-Grabot, Laurent Groc, Erwan Bezard
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Research Article Genetics

PSD-95 expression controls l-DOPA dyskinesia through dopamine D1 receptor trafficking

Abstract

l-DOPA–induced dyskinesia (LID), a detrimental consequence of dopamine replacement therapy for Parkinson’s disease, is associated with an alteration in dopamine D1 receptor (D1R) and glutamate receptor interactions. We hypothesized that the synaptic scaffolding protein PSD-95 plays a pivotal role in this process, as it interacts with D1R, regulates its trafficking and function, and is overexpressed in LID. Here, we demonstrate in rat and macaque models that disrupting the interaction between D1R and PSD-95 in the striatum reduces LID development and severity. Single quantum dot imaging revealed that this benefit was achieved primarily by destabilizing D1R localization, via increased lateral diffusion followed by increased internalization and diminished surface expression. These findings indicate that altering D1R trafficking via synapse-associated scaffolding proteins may be useful in the treatment of dyskinesia in Parkinson’s patients.

Authors

Gregory Porras, Amandine Berthet, Benjamin Dehay, Qin Li, Laurent Ladepeche, Elisabeth Normand, Sandra Dovero, Audrey Martinez, Evelyne Doudnikoff, Marie-Laure Martin-Négrier, Qin Chuan, Bertrand Bloch, Daniel Choquet, Eric Boué-Grabot, Laurent Groc, Erwan Bezard

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Figure 3

shPSD LV reduces PSD-95 levels in the MPTP-treated macaque.

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shPSD LV reduces PSD-95 levels in the MPTP-treated macaque. (A) 3 human ...
(A) 3 human shRNA sequences (sh624, sh627, and sh628) were tested separately or together (mix) in neuroblastoma human cells. sh627, sh628, and the mix of the 3 shRNAs displayed a significant reduction in PSD-95 levels compared with the mock group. Integration of the sh628 sequence into a LV induced in the same cell line significantly decreased the PSD-95 level. Lanes were run on the same gel but were noncontiguous (white lines). *P < 0.05 vs. mock. (B) Representative photomicrograph of motor striatal sections infected with mock or shPSD vector. Brain sections were immunostained with an anti–PSD-95 antibody (green) to label endogenous PSD-95, and fluorescence was visualized by confocal microscopy. Quantitative staining analysis confirmed that PSD-95 expression was significantly reduced in the shPSD group, affecting most of the motor postcommissural putamen. Scale bar: 5 mm. *P < 0.05 vs. mock. (C) PSD-95 Western blot run on striata scrapped from sections close to injection site further showed that shPSD LV significantly decreased PSD-95 level. *P < 0.05 vs. mock.