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KMID : 0578320180410080742
Molecules and Cells
2018 Volume.41 No. 8 p.742 ~ p.752
Abrogation of the Circadian Nuclear Receptor REV-ERB¥á Exacerbates 6-Hydroxydopamine-Induced Dopaminergic Neurodegeneration
Kim Jeong-Ah

Jang Sang-Won
Choi Mi-Jung
Chung Soo-Young
Choe Young-Shik
Choe Han-Kyoung
Son Gi-Hoon
Rhee Kun-Soo
Kim Kyung-Jin
Abstract
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-ERB¥á, 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-ERB¥á 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-ERB¥á 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-ERB¥á 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-erb¥á knockout mice showed prolonged microglial activation in the SN along with the overproduction of interleukin 1¥â, a pro-inflammatory cytokine, in response to 6-OHDA. In conclusion, the present study demonstrates for the first time that genetic abrogation of REV-ERB¥á 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.
KEYWORD
6-hydroxydoapmine, neurodegeneration, circadian clock, Parkinson¡¯s disease, REV-ERB¥á
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