title: 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.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France.
authors.forename: Gregory
authors.initials: G
authors.lastname: Porras
authors.forename: Amandine
authors.initials: A
authors.lastname: Berthet
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dehay
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.forename: Laurent
authors.initials: L
authors.lastname: Ladepeche
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Normand
authors.forename: Sandra
authors.initials: S
authors.lastname: Dovero
authors.forename: Audrey
authors.initials: A
authors.lastname: Martinez
authors.forename: Evelyne
authors.initials: E
authors.lastname: Doudnikoff
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Martin-Négrier
authors.forename: Qin
authors.initials: Q
authors.lastname: Chuan
authors.forename: Bertrand
authors.initials: B
authors.lastname: Bloch
authors.forename: Daniel
authors.initials: D
authors.lastname: Choquet
authors.forename: Eric
authors.initials: E
authors.lastname: Boué-Grabot
authors.forename: Laurent
authors.initials: L
authors.lastname: Groc
authors.forename: Erwan
authors.initials: E
authors.lastname: Bezard
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D000076122:Disks Large Homolog 4 Protein; D004409:Dyskinesia, Drug-Induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007980:Levodopa / Q000009:adverse effects* / Q000494:pharmacology; D008251:Macaca; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000378:metabolism*
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017447:Receptors, Dopamine D1; D007980:Levodopa