Document Detail


PSD-95 expression controls L-DOPA dyskinesia through dopamine D1 receptor trafficking.
MedLine Citation:
PMID:  23041629     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-10-08
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  122     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-01     Completed Date:  2013-01-15     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3977-89     Citation Subset:  AIM; IM    
Affiliation:
Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France.
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MeSH Terms
Descriptor/Qualifier:
Animals
Corpus Striatum / metabolism*,  pathology
Dyskinesia, Drug-Induced / genetics,  metabolism*,  pathology
HEK293 Cells
Humans
Intracellular Signaling Peptides and Proteins / genetics,  metabolism*
Levodopa / adverse effects*,  pharmacology
Macaca
Male
Membrane Proteins / genetics,  metabolism*
Parkinson Disease / genetics,  metabolism,  pathology,  therapy
Protein Transport / drug effects
Rats
Rats, Sprague-Dawley
Receptors, Dopamine D1 / genetics,  metabolism*
Synapses / genetics,  metabolism*
Chemical
Reg. No./Substance:
0/Dlgh4 protein, rat; 0/Intracellular Signaling Peptides and Proteins; 0/Levodopa; 0/Membrane Proteins; 0/Receptors, Dopamine D1
Comments/Corrections

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