PSD-95 expression controls l-DOPA dyskinesia through dopamine D1 receptor trafficking
Gregory Porras, … , Laurent Groc, Erwan Bezard
Gregory Porras, … , Laurent Groc, Erwan Bezard
Published October 8, 2012
Citation Information: J Clin Invest. 2012;122(11):3977-3989. https://doi.org/10.1172/JCI59426.
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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 1

Increased PSD-95 levels in dyskinetic monkeys and coimmunoprecipitation with D1R.

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Increased PSD-95 levels in dyskinetic monkeys and coimmunoprecipitation ...
(A) Representative Western blot using anti–PSD-95 and tubulin antibodies from putamen extracts of the different experimental groups (see Supplemental Figure 1). Bar graph represents the relative intensity of the PSD-95/tubulin ratio. Endogenous PSD-95 was significantly increased in the putamen of dyskinetic versus control monkeys. Lanes were run on the same gel but were noncontiguous (white lines). *P < 0.05 vs. control. (B) Association between PSD-95 and D1R in monkey striatum. Western blots with anti–PSD-95 or anti-D1 antibodies revealed that PSD-95 and D1R from extracts of dyskinetic monkey striatum tissues coimmunoprecipitated with anti-D1R and anti-PSD antibodies, respectively. No band was detected in absence of antibodies (C, control).