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- Title
PSD-95 expression controls L-DOPA dyskinesia through dopamine D1 receptor trafficking.
- Authors
Porras, Gregory; Berthet, Amandine; Dehay, Benjamin; Qin Li; Ladepeche, Laurent; Normand, Elisabeth; Dovero, Sandra; Martinez, Audrey; Doudnikoff, Evelyne; Martin-Négrier, Marie-Laure; Qin Chuan; Bloch, Bertrand; Choquet, Daniel; Boué-Grabot, Eric; Groc, Laurent; Bezard, Erwan
- Abstract
L-DOPA-induced dyskinesia (LID), a detrimental consequence of dopamine replacement therapy for Parkin-son's disease, is associated with an alteration in dopamine D1 receptor (D1R) and glutamate receptor interac-tions. 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.
- Subjects
PARKINSON'S disease treatment; GENE expression; DOPAMINE receptors; MOVEMENT disorders; LABORATORY rats; GLUTAMATE receptors; PATIENTS
- Publication
Journal of Clinical Investigation, 2012, Vol 122, Issue 11, p3977
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI59426