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PMID:23041629

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Citation

Porras, G, 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 and Bezard, E (2012) PSD-95 expression controls L-DOPA dyskinesia through dopamine D1 receptor trafficking. J. Clin. Invest. 122:3977-89

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.

Links

PubMed PMC3484432 Online version:10.1172/JCI59426

Keywords

Animals; Corpus Striatum/metabolism; Corpus Striatum/pathology; Dyskinesia, Drug-Induced/genetics; Dyskinesia, Drug-Induced/metabolism; Dyskinesia, Drug-Induced/pathology; HEK293 Cells; Humans; Intracellular Signaling Peptides and Proteins/genetics; Intracellular Signaling Peptides and Proteins/metabolism; Levodopa/adverse effects; Levodopa/pharmacology; Macaca; Male; Membrane Proteins/genetics; Membrane Proteins/metabolism; Parkinson Disease/genetics; Parkinson Disease/metabolism; Parkinson Disease/pathology; Parkinson Disease/therapy; Protein Transport/drug effects; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1/genetics; Receptors, Dopamine D1/metabolism; Synapses/genetics; Synapses/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:DRD1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:68424

F

Seeded From UniProt

complete

RAT:DLG4

enables

GO:0031748: D1 dopamine receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:2518

F

Seeded From UniProt

complete

Notes

See also

References

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