title: D1 dopamine receptor stimulation impairs striatal proteasome activity in Parkinsonism through 26S proteasome disassembly.
abstract: Among the mechanisms underlying the development of L-dopa-induced dyskinesia (LID) in Parkinson's disease, complex alterations in dopamine signaling in D1 receptor (D1R)-expressing medium spiny striatal neurons have been unraveled such as, but not limited to, dysregulation of D1R expression, lateral diffusion, intraneuronal trafficking, subcellular localization and desensitization, leading to a pathological anchorage of D1R at the plasma membrane. Such anchorage is partly due to a decreased proteasomal activity that is specific of the L-dopa-exposed dopamine-depleted striatum, results from D1R activation and feeds-back the D1R exaggerated cell surface abundance. The precise mechanisms by which L-dopa affects striatal proteasome activity remained however unknown. We here show, in a series of in vitro ex vivo and in vivo models, that such rapid modulation of striatal proteasome activity intervenes through D1R-mediated disassembly of the 26S proteasome rather than change in transcription or translation of proteasome or proteasome subunits intraneuronal relocalization.
authors.affiliation: Univ. de Bordeaux, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
authors.forename: Pedro
authors.initials: P
authors.lastname: Barroso-Chinea
authors.affiliation: Univ. de Bordeaux, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Thiolat
authors.affiliation: Univ. de Bordeaux, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
authors.forename: Simone
authors.initials: S
authors.lastname: Bido
authors.affiliation: Univ. de Bordeaux, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Martinez
authors.affiliation: Univ. de Bordeaux, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Doudnikoff
authors.affiliation: Univ. de Bordeaux, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Baufreton
authors.affiliation: Univ. de Bordeaux, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bourdenx
authors.affiliation: Univ. de Bordeaux, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Bloch
authors.affiliation: Univ. de Bordeaux, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France. Electronic address: erwan.bezard@u-bordeaux.fr.
authors.forename: Erwan
authors.initials: E
authors.lastname: Bezard
authors.affiliation: Univ. de Bordeaux, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Martin-Negrier
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000201:enzymology / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism*
chemical_list: D001552:Benzazepines; D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; C071262:SK&F 82958; D046988:Proteasome Endopeptidase Complex
keywords: Catalytic activity; Cellular localization; Dopamine D1 receptor; Dyskinesia; Membrane anchoring; Proteasome; Unit dissociations