D1 dopamine receptor stimulation impairs striatal proteasome activity in Parkinsonism through 26S proteasome disassembly

• Main Authors: Pedro Barroso-Chinea, Marie-Laure Thiolat, Simone Bido, Audrey Martinez, Evelyne Doudnikoff, Jérôme Baufreton, Mathieu Bourdenx, Bertrand Bloch, Erwan Bezard, Marie-Laure Martin-Negrier
• Format: Article
• Language: English
• Published: Elsevier 2015-06-01
• Series: Neurobiology of Disease
• Subjects: Dopamine D1 receptor; Dyskinesia; Cellular localization; Membrane anchoring; Proteasome; Catalytic activity
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996115000595

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.