Abrogation of the circadian nuclear receptor REV-ERBα exacerbates 6-hydroxydopamine-induced dopaminergic neurodegeneration

Jeongah Kim, Sangwon Jang, Mijung Choi, Sooyoung Chung, Youngshik Choe, Han Kyoung Choe, Gi Hoon Son, Kunsoo Rhee, Kyungjin Kim

Research output: Contribution to journalArticle

2 Citations (Scopus)

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-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.

Original languageEnglish
Pages (from-to)742-752
Number of pages11
JournalMolecules and Cells
Volume41
Issue number8
DOIs
Publication statusPublished - 2018 Jan 1

Fingerprint

Oxidopamine
Cytoplasmic and Nuclear Receptors
Parkinson Disease
Dopaminergic Neurons
Substantia Nigra
Ventral Tegmental Area
Circadian Clocks
Mesencephalon
Interleukin-1
Knockout Mice
Neurodegenerative Diseases
Disease Progression
Cytokines
Phenotype
Neurons
Injections
Population
Genes

Keywords

  • 6-hydroxydoapmine
  • Circadian clock
  • Neurodegeneration
  • Parkinson’s disease
  • REV-ERBα

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Abrogation of the circadian nuclear receptor REV-ERBα exacerbates 6-hydroxydopamine-induced dopaminergic neurodegeneration. / Kim, Jeongah; Jang, Sangwon; Choi, Mijung; Chung, Sooyoung; Choe, Youngshik; Choe, Han Kyoung; Son, Gi Hoon; Rhee, Kunsoo; Kim, Kyungjin.

In: Molecules and Cells, Vol. 41, No. 8, 01.01.2018, p. 742-752.

Research output: Contribution to journalArticle

Kim, Jeongah ; Jang, Sangwon ; Choi, Mijung ; Chung, Sooyoung ; Choe, Youngshik ; Choe, Han Kyoung ; Son, Gi Hoon ; Rhee, Kunsoo ; Kim, Kyungjin. / Abrogation of the circadian nuclear receptor REV-ERBα exacerbates 6-hydroxydopamine-induced dopaminergic neurodegeneration. In: Molecules and Cells. 2018 ; Vol. 41, No. 8. pp. 742-752.
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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-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.",
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AU - Chung, Sooyoung

AU - Choe, Youngshik

AU - Choe, Han Kyoung

AU - Son, Gi Hoon

AU - Rhee, Kunsoo

AU - Kim, Kyungjin

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AB - 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.

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