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Exp Neurol. 2018 Jun;304:143-153. doi: 10.1016/j.expneurol.2018.03.008. Epub 2018 Mar 9.

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

Author information

1
Axe Neuroscience, Centre de Recherche du CHU de Québec, Université Laval, Québec, Canada; Département de Psychiatrie & Neuroscience, Université Laval, Québec, Canada.
2
Axe Neuroscience, Centre de Recherche du CHU de Québec, Université Laval, Québec, Canada.
3
Faculté de Pharmacie, Université de Montréal, Montréal, Canada.
4
Faculté de Pharmacie, Université de Montréal, Montréal, Canada; Groupe de recherche sur le système nerveux central (GRSNC), Université de Montréal, Montréal, Canada. Electronic address: daniel.levesque.1@umontreal.ca.

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.

KEYWORDS:

Dopamine denervation; Knockout mice; Mutant transgenic rat; NGFI-B; Nuclear receptor; Striatum; Substantia nigra; Transcription factor

PMID:
29530712
DOI:
10.1016/j.expneurol.2018.03.008
[Indexed for MEDLINE]

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