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

  • Kim, Jeongah (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Jang, Sangwon (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Choi, Mijung (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Chung, Sooyoung (Department of Brain and Cognitive Sciences, Scranton College, Ewha Womans University) ;
  • Choe, Youngshik (Korea Brain Research Institute (KBRI)) ;
  • Choe, Han Kyoung (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Son, Gi Hoon (Department of Biomedical Sciences, College of Medicine, Korea University) ;
  • Rhee, Kunsoo (Department of Biological Sciences, College of Natural Sciences, Seoul National University) ;
  • Kim, Kyungjin (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST))
  • Received : 2018.05.09
  • Accepted : 2018.06.18
  • Published : 2018.08.31


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 $REV-ERB{\alpha}$, 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 $REV-ERB{\alpha}$ 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 $REV-ERB{\alpha}$ affects PD-related phenotypes in a mouse model of PD produced by a unilateral injection of 6-hydroxydopamine (6-OHDA) into the dorsal striatum. $REV-ERB{\alpha}$ 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 $REV-erb{\alpha}$ knockout mice showed prolonged microglial activation in the SN along with the over-production of interleukin $1{\beta}$, a pro-inflammatory cytokine, in response to 6-OHDA. In conclusion, the present study demonstrates for the first time that genetic abrogation of $REV-ERB{\alpha}$ 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.


Supported by : National Research Foundation of Korea, DGIST


  1. Abbott, R., Ross, G., White, L., Tanner, C., Masaki, K., Nelson, J., Curb, J., and Petrovitch, H. (2005). Excessive daytime sleepiness and subsequent development of Parkinson disease. Neurology 65, 1442-1446.
  2. Akiyama, H., and McGeer, P.L. (1989). Microglial response to 6-hydroxydopamine-induced substantia nigra lesions. Brain Res. 489, 247-253.
  3. Alvarez-Fischer, D., Henze, C., Strenzke, C., Westrich, J., Ferger, B., Hoglinger, G.U., Oertel, W.H., and Hartmann, A. (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.
  4. Banerjee, S., Wang, Y., Solt, L.A., Griffett, K., Kazantzis, M., Amador, A., El-Gendy, B.M., Huitron-Resendiz, S., Roberts, A.J., Shin, Y., et al. (2014). Pharmacological targeting of the mammalian clock regulates sleep architecture and emotional behaviour. Nat. Commun. 5, 5759.
  5. Bechtold, D.A., Gibbs, J.E., and Loudon, A.S. (2010). Circadian dysfunction in disease. Trends. Pharmacol. Sci. 31, 191-198.
  6. Blum-Degena, D., Muller, T., Kuhn, W., Gerlach, M., Przuntek, H., and Riederer, P. (1995). Interleukin-1${\beta}$ and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's and de novo Parkinson's disease patients. Neurosci. Lett. 202, 17-20.
  7. Breen, D.P., Vuono, R., Nawarathna, U., Fisher, K., Shneerson, J.M., Reddy, A.B., and Barker, R.A. (2014). Sleep and circadian rhythm regulation in early Parkinson disease. JAMA Neurol. 71, 589-595.
  8. Chung, S., Lee, E.J., Yun, S., Choe, H.K., Park, S.B., Son, H.J., Kim, K.S., Dluzen, D.E., Lee, I., Hwang, O., et al. (2014). Impact of circadian nuclear receptor REV-ERBalpha on midbrain dopamine production and mood regulation. Cell 157, 858-868.
  9. Comella, C.L. (2006). Sleep disturbances and excessive daytime sleepiness in Parkinson disease: an overview. J. Neural Transm. Suppl. 70, 349-355.
  10. Dauer, W., and Przedborski, S. (2003). Parkinson's disease: mechanisms and models. Neuron 39, 889-909.
  11. Everett, L.J., and Lazar, M.A. (2014). Nuclear receptor Rev-erb${\alpha}$: up, down, and all around. Trends. Endocrinol. Metab. 25, 586-592.
  12. Ferrari, C.C., Godoy, M.C.P., Tarelli, R., Chertoff, M., Depino, A.M., and Pitossi, F.J. (2006). Progressive neurodegeneration and motor disabilities induced by chronic expression of IL-1${\beta}$ in the substantia nigra. Neurobiol. Dis. 24, 183-193.
  13. Fifel, K., Vezoli, J., Dzahini, K., Claustrat, B., Leviel, V., Kennedy, H., Procyk, E., Dkhissi-Benyahya, O., Gronfier, C., and Cooper, H.M. (2014). Alteration of daily and circadian rhythms following dopamine depletion in MPTP treated non-human primates. PLoS One 9, e86240.
  14. Fonken, L.K., Frank, M.G., Kitt, M.M., Barrientos, R.M., Watkins, L.R., and Maier, S.F. (2015). Microglia inflammatory responses are controlled by an intrinsic circadian clock. Brain Behav. Immun. 45, 171-179.
  15. Gibbs, J.E., Blaikley, J., Beesley, S., Matthews, L., Simpson, K.D., Boyce, S.H., Farrow, S.N., Else, K.J., Singh, D., Ray, D.W., et al. (2012). The nuclear receptor REV-ERB${\alpha}$ mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines. Proc. Natl. Acad. Sci. USA 109, 582-587.
  16. Gu, Z., Wang, B., Zhang, Y.B., Ding, H., Zhang, Y., Yu, J., Gu, M., Chan, P., and Cai, Y. (2015). Association of ARNTL and PER1 genes with Parkinson's disease: a case-control study of Han Chinese. Sci. Rep. 5, 15891.
  17. Guillaumond, F., Dardente, H., Giguere, V., and Cermakian, N. (2005). Differential control of Bmal1 circadian transcription by REVERB and ROR nuclear receptors. J. Biol. Rhythms 20, 391-403.
  18. Haas, S.J., Zhou, X., Machado, V., Wree, A., Krieglstein, K., and Spittau, B. (2016). Expression of Tgfbeta1 and Inflammatory Markers in the 6-hydroxydopamine Mouse Model of Parkinson's Disease. Front. Mol. Neurosci. 9, 7.
  19. Hayashi, A., Matsunaga, N., Okazaki, H., Kakimoto, K., Kimura, Y., Azuma, H., Ikeda, E., Shiba, T., Yamato, M., Yamada, K.i., et al. (2013). A disruption mechanism of the molecular clock in a MPTP mouse model of Parkinson's disease. Neuromol. Med. 15, 238-251.
  20. Hirsch, E.C., and Hunot, S. (2009). Neuroinflammation in Parkinson's disease: a target for neuroprotection? Lancet Neurol. 8, 382-397.
  21. Keller, M., Mazuch, J., Abraham, U., Eom, G.D., Herzog, E.D., Volk, H.D., Kramer, A., and Maier, B. (2009). A circadian clock in macrophages controls inflammatory immune responses. Proc. Natl. Acad. Sci. USA 106, 21407-21412.
  22. Kim, T.W., Moon, Y., Kim, K., Lee, J.E., Koh, H.C., Kim, H., and Sun, W. (2011). Dissociation of progressive dopaminergic neuronal death and behavioral impairments by Bax deletion in a mouse model of Parkinson's diseases. PloS One 6, e25346.
  23. Kojetin, D., Wang, Y., Kamenecka, T.M., and Burris, T.P. (2010). Identification of SR8278, a synthetic antagonist of the nuclear heme receptor REV-ERB. ACS Chem. Biol. 6, 131-134.
  24. Kondratova, A.A., and Kondratov, R.V. (2012). Circadian clock and pathology of the ageing brain. Nat. Rev. Neurosci. 13, 325.
  25. Kudo, T., Loh, D.H., Truong, D., Wu, Y., and Colwell, C.S. (2011). Circadian dysfunction in a mouse model of Parkinson's disease. Exp. Neurol. 232, 66-75.
  26. Lauretti, E., Di Meco, A., Merali, S., and Pratico, D. (2017). Circadian rhythm dysfunction: a novel environmental risk factor for Parkinson's disease. Mol. Psychiatry 22, 280-286.
  27. Mang, G.M., La Spada, F., Emmenegger, Y., Chappuis, S., Ripperger, J.A., Albrecht, U., and Franken, P. (2016). Altered Sleep Homeostasis in Rev-erb ${\alpha}$ Knockout Mice. Sleep 39, 589-601.
  28. Marinova-Mutafchieva, L., Sadeghian, M., Broom, L., Davis, J.B., Medhurst, A.D., and Dexter, D.T. (2009). Relationship between microglial activation and dopaminergic neuronal loss in the substantia nigra: a time course study in a 6-hydroxydopamine model of Parkinson's disease. J. Neurochem. 110, 966-975.
  29. McGeer, P., Itagaki, S., Boyes, B., and McGeer, E. (1988). Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 38, 1285-1285.
  30. Mogi, M., Harada, M., Kondo, T., Riederer, P., Inagaki, H., Minami, M., and Nagatsu, T. (1994a). Interleukin-1${\beta}$, interleukin-6, epidermal growth factor and transforming growth factor-${\alpha}$ are elevated in the brain from parkinsonian patients. Neurosci. Lett. 180, 147-150.
  31. Mogi, M., Harada, M., Riederer, P., Narabayashi, H., Fujita, K., and Nagatsu, T. (1994b). Tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci. Lett. 165, 208-210.
  32. Monville, C., Torres, E.M., and Dunnett, S.B. (2006). Comparison of incremental and accelerating protocols of the rotarod test for the assessment of motor deficits in the 6-OHDA model. J. Neurosci. Methods 158, 219-223.
  33. Musiek, E.S., Lim, M.M., Yang, G., Bauer, A.Q., Qi, L., Lee, Y., Roh, J.H., Ortiz-Gonzalez, X., Dearborn, J.T., Culver, J.P., et al. (2013). Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. J. Clin. Invest. 123, 5389-5400.
  34. Nguyen, K.D., Fentress, S.J., Qiu, Y., Yun, K., Cox, J.S., and Chawla, A. (2013). Circadian gene Bmal1 regulates diurnal oscillations of Ly6C(hi) inflammatory monocytes. Science 341, 1483-1488.
  35. Preitner, N., Damiola, F., Zakany, J., Duboule, D., Albrecht, U., and Schibler, U. (2002). The orphan nuclear receptor REV-ERB${\alpha}$ controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110, 251-260.
  36. Sauer, H., and Oertel, W. (1994). Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 59, 401-415.
  37. Solt, L.A., Wang, Y., Banerjee, S., Hughes, T., Kojetin, D.J., Lundasen, T., Shin, Y., Liu, J., Cameron, M.D., Noel, R., et al. (2012). Regulation of circadian behavior and metabolism by synthetic REV-ERB agonists. Nature 485, 62-68.
  38. Tansey, M.G., and Goldberg, M.S. (2010). Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol. Dis. 37, 510-518.
  39. Videnovic, A., Lazar, A.S., Barker, R.A., and Overeem, S. (2014). 'The clocks that time us'-circadian rhythms in neurodegenerative disorders. Nat. Rev. Neurol. 10, 683-693.
  40. Virgone-Carlotta, A., Uhlrich, J., Akram, M.N., Ressnikoff, D., Chretien, F., Domenget, C., Gherardi, R., Despars, G., Jurdic, P., Honnorat, J., et al. (2013). Mapping and kinetics of microglia/neuron cell-to-cell contacts in the 6-OHDA murine model of Parkinson's disease. Glia 61, 1645-1658.
  41. Walsh, S., Finn, D., and Dowd, E. (2011). Time-course of nigrostriatal neurodegeneration and neuroinflammation in the 6-hydroxydopamine-induced axonal and terminal lesion models of Parkinson's disease in the rat. Neuroscience 175, 251-261.
  42. Warner, T.T., and Schapira, A.H. (2003). Genetic and environmental factors in the cause of Parkinson's disease. Ann. Neurol. 53 Suppl 3, S16-23.
  43. Woldt, E., Sebti, Y., Solt, L.A., Duhem, C., Lancel, S., Eeckhoute, J., Hesselink, M.K., Paquet, C., Delhaye, S., Shin, Y., et al. (2013). Reverb-${\alpha}$ modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy. Nat. Med. 19, 1039-1046.

Cited by

  1. Small Molecule Modulators of the Circadian Molecular Clock With Implications for Neuropsychiatric Diseases vol.11, pp.1662-5099, 2019,