Abrogation of the Circadian Nuclear Receptor REV-ERBα Exacerbates 6-Hydroxydopamine-Induced Dopaminergic Neurodegeneration

김정아; 장상원; 최미정; 정수영; 최영식; 최한경; 손기훈; 이건수; 김경진

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저자정보: 김정아 (서울대학교) 장상원 (대구경북과학기술원) 최미정 (대구경북과학기술원) 정수영 (이화여자대학교) 최영식 (한국뇌연구원) 최한경 (대구경북과학기술원) 손기훈 (고려대학교) 이건수 (서울대학교) 김경진 (대구경북과학기술원)

저널정보: 한국분자세포생물학회 Molecules and Cells Molecules and Cells 제41권 제8호

발행연도: 2018.8

수록면: 742 - 752 (11page)

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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 (6OHDA) 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-erb α 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.

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, a circadian nuclear receptor, serves as a key molecular link between the circadian and DAergic systems. It competitively cooperates with NURR1, another nuclear receptor requiParkinson’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 (6OHDA) 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-erb α 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.red for the optimal development and function of DA neurons, to control DAergic gene transcription. Considering our previous findings, we hypothesize that REV-ERB? 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? 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? 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? knockout mice showed prolonged microglial activation in the SN along with the overproduction of interleukin 1, 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 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.

#6-hydroxydoapmine #neurodegeneration #circadian clock #Parkinson's disease #REV-ERBα

참고문헌 (43)

참고문헌 신청

Abbott, R. / 2005 / Excessive daytime sleepiness and subsequent development of Parkinson disease / Neurology 65:1442~1446

Akiyama, H. / 1989 / Microglial response to 6-hydroxydopamine-induced substantia nigra lesions / Brain Res 489:247~253

Alvarez-Fischer, D. / 2008 / Characterization of the striatal 6-OHDA model of Parkinson's disease in wild type and ${\alpha}$-synuclein-deleted mice / Exp. Neurol. 210:182~193

Banerjee, S. / 2014 / Pharmacological targeting of the mammalian clock regulates sleep architecture and emotional behaviour / Nat. Commun. 5:5759

Bechtold, D.A. / 2010 / Circadian dysfunction in disease / Trends. Pharmacol. Sci. 31:191~198

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Jeongah Kim

소속기관 Department of Anatomy College of Medicine Korea University

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Kim Kyungjin

소속기관 Daegu Gyeongbuk Institute of Science and Technology (DGIST)

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