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: Pedro Barroso-Chinea, Marie-Laure Thiolat, Simone Bido, Audrey Martinez, Evelyne Doudnikoff, Jérôme Baufreton, Mathieu Bourdenx, Bertrand Bloch, Erwan Bezard, Marie-Laure Martin-Negrier
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 78 Pg. 77-87 (Jun 2015) ISSN: 1095-953X [Electronic] United States
• PMID: 25766677 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Benzazepines
• Dopamine Agonists
• Receptors, Dopamine D1
• SK&F 82958
• Proteasome Endopeptidase Complex

Topics

• Animals
• Benzazepines (pharmacology)
• Cells, Cultured
• Corpus Striatum (drug effects, enzymology, metabolism)
• Dopamine Agonists (pharmacology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neurons (drug effects, metabolism)
• Parkinsonian Disorders (enzymology, metabolism)
• Proteasome Endopeptidase Complex (drug effects, metabolism)
• Rats, Sprague-Dawley
• Receptors, Dopamine D1 (metabolism)