PSD-95 expression controls L-DOPA dyskinesia through dopamine D1 receptor trafficking
J. Clin. Invest.. 2012-10-08; 122(11): 3977-3989
DOI: 10.1172/JCI59426
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1. J Clin Invest. 2012 Nov;122(11):3977-89. doi: 10.1172/JCI59426. Epub 2012 Oct 8.
PSD-95 expression controls L-DOPA dyskinesia through dopamine D1 receptor
trafficking.
Porras G(1), Berthet A, Dehay B, Li Q, Ladepeche L, Normand E, Dovero S, Martinez
A, Doudnikoff E, Martin-Négrier ML, Chuan Q, Bloch B, Choquet D, Boué-Grabot E,
Groc L, Bezard E.
Author information:
(1)Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux,
France.
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.
DOI: 10.1172/JCI59426
PMCID: PMC3484432
PMID: 23041629 [Indexed for MEDLINE]