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 4

Reducing PSD-95 in the MPTP-treated macaque markedly alleviates dyskinesia.

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Reducing PSD-95 in the MPTP-treated macaque markedly alleviates dyskines...
(A, C, and E) Time course of clinical ratings (median) and locomotor activity counts (mean). Data are shown without SEM for readability. l-DOPA or amantadine administration began at 0 minutes. (A) shPSD had no effect on l-DOPA–induced parkinsonian disability score at any time point. (B) Area under the curve (AUC) analysis of parkinsonian disability scores confirmed this lack of effect. Orange bar denotes the presurgery score of the entire population. (C) LID severity was affected by shPSD and/or pharmacological treatment. *P < 0.05 vs. l-DOPA–treated mock (bracket colors correspond with respective groups to show time frame of significance). (D) The overall positive effect of shPSD and/or pharmacological treatment on LID severity was further demonstrated by the AUC data. *P < 0.05 vs. l-DOPA–treated mock; #P < 0.05 vs. l-DOPA–treated shPSD. Orange bar denotes the presurgery score of the entire population. (E and F) Consequently, locomotor activity was lower in shPSD animals receiving l-DOPA alone and in both groups when receiving l-DOPA plus amantadine. Orange bar denotes the presurgery count for the entire population. *P < 0.05 vs. l-DOPA–treated mock; #P < 0.05 vs. l-DOPA–treated shPSD. (G) On-time was not affected by any treatment. (H) shPSD significantly increased Good On-time. *P < 0.05 vs. l-DOPA–treated mock. (I) Bad On-time was reduced in shPSD animals receiving l-DOPA alone and in both groups when receiving l-DOPA plus amantadine. *P < 0.05 vs. l-DOPA–treated mock.