title: L-DOPA impairs proteasome activity in parkinsonism through D1 dopamine receptor.
abstract: Aberrant membrane localization of dopamine D(1) receptor (D1R) is associated with L-DOPA-induced dyskinesia (LID), a major complication of L-DOPA treatment in Parkinson's disease (PD). Since the proteasome plays a central role in modulating neuronal response through regulation of neurotransmitter receptor intraneuronal fate, we hypothesized that the ubiquitine-proteasome proteolytic pathway could be impaired in LID. Those LIDs are actually associated with a striatum-specific decrease in proteasome catalytic activity and accumulation of polyubiquitinated proteins in experimental rodent and monkey parkinsonism. We then demonstrated that such decreased proteasome catalytic activity (1) results from D1R activation and (2) feed-back the D1R abnormal trafficking, i.e., its exaggerated cell surface abundance. We further showed that the genetic invalidation of the E3 ubiquitin-protein ligase parkin PD gene leads to exaggerated abnormal involuntary movements compared with wild-type mice. We thus established in an unprecedented series of experimental models that impairment of the ubiquitine-proteasome system at specific nodes (E3 ligase parkin, polyubiquitination, proteasome catalytic activity) leads to the same phenomenon, i.e., aberrant behavioral response to dopamine replacement therapy in PD, highlighting the intimate interplay between dopamine receptor and proteasome activity in a nondegenerative context.
authors.affiliation: Université Victor Segalen-Bordeaux 2, Centre National de la Recherche Scientifique, Institute of Neurodegenerative Diseases, 33076 Bordeaux, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Berthet
authors.forename: Erwan
authors.initials: E
authors.lastname: Bezard
authors.forename: Gregory
authors.initials: G
authors.lastname: Porras
authors.forename: Stefania
authors.initials: S
authors.lastname: Fasano
authors.forename: Pedro
authors.initials: P
authors.lastname: Barroso-Chinea
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dehay
authors.forename: Audrey
authors.initials: A
authors.lastname: Martinez
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Thiolat
authors.forename: Marika
authors.initials: M
authors.lastname: Nosten-Bertrand
authors.forename: Bruno
authors.initials: B
authors.lastname: Giros
authors.forename: Jérôme
authors.initials: J
authors.lastname: Baufreton
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.forename: Bertrand
authors.initials: B
authors.lastname: Bloch
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Martin-Negrier
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000633:toxicity; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D007980:Levodopa / Q000633:toxicity*; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000502:physiology
chemical_list: D018491:Dopamine Agonists; D061988:Proteasome Inhibitors; D017447:Receptors, Dopamine D1; D007980:Levodopa; D046988:Proteasome Endopeptidase Complex