Genetic disruption of the nuclear receptor Nur77 (Nr4a1) in rat reduces dopamine cell loss and l-Dopa-induced dyskinesia in experimental Parkinson's disease.

TitleGenetic disruption of the nuclear receptor Nur77 (Nr4a1) in rat reduces dopamine cell loss and l-Dopa-induced dyskinesia in experimental Parkinson's disease.
Publication TypeJournal Article
Year of Publication2018
AuteursRouillard, C, Baillargeon, J, Paquet, B, St-Hilaire, M, Maheux, J, Lévesque, C, Darlix, N, Majeur, S, Lévesque, D
JournalExp Neurol
Volume304
Pagination143-153
Date Published2018 Jun
ISSN1090-2430
Abstract

Parkinson's disease (PD) is an idiopathic progressive neurodegenerative disorder characterized by the loss of midbrain dopamine neurons. Levodopa (l-dopa) is the main pharmacological approach to relieve PD motor symptoms. However, chronic treatment with l-Dopa is inevitably associated with the generation of abnormal involuntary movements (l-Dopa-induced dyskinesia). We have previously shown that Nr4a1 (Nur77), a transcription factor of the nuclear receptor family, is closely associated with dopamine neurotransmission in the mature brain. However, the role of Nr4a1 in the etiology of PD and its treatment remain elusive. We report here that the neurotoxin 6-hydroxydopamine in rat lead to a rapid up-regulation of Nr4a1 in the substantia nigra. Genetic disruption of Nr4a1 in rat reduced neurotoxin-induced dopamine cell loss and l-Dopa-induced dyskinesia, whereas virally-driven striatal overexpression of Nr4a1 enhanced or partially restored involuntary movements induced by chronic l-Dopa in wild type and Nr4a1-deficient rats, respectively. Collectively, these results suggest that Nr4a1 is involved in dopamine cell loss and l-Dopa-induced dyskinesia in experimental PD.

DOI10.1016/j.expneurol.2018.03.008
Alternate JournalExp. Neurol.
PubMed ID29530712
Grant ListP51 OD011132 / OD / NIH HHS / United States