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

作者：Barroso Chinea Pedro; Thiolat Marie Laure; Bido Simone; Martinez Audrey; Doudnikoff Evelyne; Baufreton Jerome; Bourdenx Mathieu; Bloch Bertrand; Bezard Erwan^*; Martin Negrier Marie Laure

来源：Neurobiology of Disease, 2015, 78: 77-87.

DOI：10.1016/j.nbd.2015.02.024

• Dopamine D1 receptor
• Dyskinesia
• Cellular localization
• Membrane anchoring
• Proteasome
• Catalytic activity
• Unit dissociations

Among the mechanisms underlying the development of L-dopa-induced dyskinesia (UD) 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.

• 出版日期2015-6