Abrogation of the Circadian Nuclear Receptor REV-ERBα Exacerbates 6-Hydroxydopamine- Induced Dopaminergic Neurodegeneration
Jeongah Kim1,2, Sangwon Jang1, Mijung Choi1, Sooyoung Chung3, Youngshik Choe4, Han Kyoung
Choe1,4, Gi Hoon Son5, Kunsoo Rhee2, and Kyungjin Kim1,4,*
1Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea,2Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Korea, 3Department of Brain and Cognitive Sciences, Scranton College, Ewha Womans University, Seoul 03760, Korea, 4Korea Brain Research Institute (KBRI), Daegu 41068, Korea, 5Department of Biomedical Sciences, College of Medicine, Korea University, Seoul 02841, Korea
*Correspondence: kyungjin@dgist.ac.kr
Received May 9, 2018; Revised June 17, 2018; Accepted June 18, 2018.; Published online July 30, 2018.
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Parkinson’s disease (PD) is a neurodegenerative disease characterized by progressive degeneration of dopaminergic (DAergic) neurons, particularly in the substantia nigra (SN). Although circadian dysfunction has been suggested as one of the pathophysiological risk factors for PD, the exact molecular link between the circadian clock and PD remains largely unclear. We have recently demonstrated that REV-ERBα, a circadian nuclear receptor, serves as a key molecular link between the circadian and DAergic systems. It competitively cooperates with NURR1, another nuclear receptor required for the optimal development and function of DA neurons, to control DAergic gene transcription. Considering our previous findings, we hypothesize that REV-ERBα may have a role in the onset and/or progression of PD. In the present study, we therefore aimed to elucidate whether genetic abrogation of REV-ERBα affects PD-related phenotypes in a mouse model of PD produced by a unilateral injection of 6-hydroxydopamine (6- OHDA) into the dorsal striatum. REV-ERBα deficiency significantly exacerbated 6-OHDA-induced motor deficits as well as DAergic neuronal loss in the vertebral midbrain including the SN and the ventral tegmental area. The exacerbated DAergic degeneration likely involves neuroinflammation-mediated neurotoxicity. The Rev-erbα knockout mice showed prolonged microglial activation in the SN along with the overproduction of interleukin 1β, a pro-inflammatory cytokine, in response to 6-OHDA. In conclusion, the present study demonstrates for the first time that genetic abrogation of REV-ERBα can increase vulnerability of DAergic neurons to neurotoxic insults, such as 6-OHDA, thereby implying that its normal function may be beneficial for maintaining DAergic
neuron populations during PD progression. 
Keywords: 6-hydroxydoapmine, neurodegeneration, circadian clock, Parkinson’s disease, REV-ERBα

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31 July 2018 Volume 41,
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