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 2

Downregulating PSD-95 in the DA-deprived striatum reduces AIM severity in the hemiparkinsonian rat.

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Downregulating PSD-95 in the DA-deprived striatum reduces AIM severity i...
(A) Both the peak AIM scores (rated at 60 minutes) from day 5 as well as the time course AIM (bottom right inset) scores were significantly reduced with shPSD LV compared with mock control. *P < 0.05, shPSD vs. mock. (B) Rats displayed identical peak AIMs after 9 l-DOPA treatment days before receiving LV at day 12 (red arrow). Peak AIM score in the shPSD group was significantly reduced compared with all other groups. This reduction was further highlighted in a time course experiment at day 27 (bottom right insets), with a significant decrease 60 and 90 minutes after l-DOPA administration. In both sets, animals had similar loss of dopaminergic innervation in the striatum as detected by TH immunohistochemistry (top left insets). *P < 0.05, shPSD vs. all other groups. (C) Detection of the endogenous PSD-95 and exogenous PSD-95–GFP transgene by Western blot in striata extracts from 2 sets of animals. Both lesioned (L) and unlesioned (UL) sides are shown. In both experiments, shPSD significantly reduced the expression of endogenous PSD-95, whereas PSD significantly increased PSD-95, compared with the mock group. Lanes were run on the same gel but were noncontiguous (white lines). *P < 0.05 vs. mock. (D) While TAT-D1-SCR peptide had no effect on AIM score, TAT-D1-CT (0.25 and 0.5 nmol) dose-dependently reduced AIM score at peak and at 60 and 90 minutes after l-DOPA administration, resulting in overall improvement. *P < 0.05 vs. vehicle.