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

Erwan Bezard and Laurent Groc of the University of Bordeaux discuss the effects of the post-synaptic density protein PSD-95 on the development of levodopa-induced dyskinesia. Highlights:

  • L-DOPA-induced dyskinesia (LID) is a major side effect of dopamine replacement therapy for Parkinson’s disease.
  • LID is associated with changes in D1 dopamine receptor (D1R) interactions at the striatal synapses.
  • Using rat and macaque models, Bezard, Groc, and colleagues demonstrated that the synaptic density protein PSD-95 alters the trafficking of D1R to the synapse.
  • Loss of PSD-95 in the striatum reduces the development and severity of LID.

Published October 8, 2012, by The JCI

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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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