Abstract
Parkinson’s disease (PD) is a common neurodegenerative disorder that is characterized by the degeneration of dopaminergic neurons in the substantia nigra and dopamine depletion in the striatum. Although the motor symptoms are still regarded as the main problem, non-motor symptoms in PD also markedly impair the quality of life. Several non-motor symptoms, such as sleep disturbances and depression, are suggested to be implicated in the alteration in circadian clock function. In this study, we investigated circadian disruption and the mechanism in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP-treated mice exhibited altered 24-h rhythms in body temperature and locomotor activity. In addition, MPTP treatment also affected the circadian clock system at the genetic level. The exposure of human neuroblastoma cells (SH-SY5Y) to 1-metyl-4-phenylpyridinium (MPP+) increased or decreased the mRNA levels of several clock genes in a dose-dependent manner. MPP+-induced changes in clock genes expression were reversed by Compound C, an inhibitor of AMP-activated protein kinase (AMPK). Most importantly, addition of ATP to the drinking water of MPTP-treated mice attenuated neurodegeneration in dopaminergic neurons, suppressed AMPK activation and prevented circadian disruption. The present findings suggest that the activation of AMPK caused circadian dysfunction, and ATP may be a novel therapeutic strategy based on the molecular clock in PD.
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Acknowledgments
This study was supported partially by Grants-in-Aid for Scientific Research on Priority Areas “Cancer” (S.O. 20014016) from the Ministry of Education, Culture, Sport, Science and Technology of Japan; for Scientific Research (B) (S.O. 21390047); for Challenging Exploratory Research (S.O. 21659041); and for the Encouragement of Young Scientists (N.M. 20790137) from the Japan Society for the Promotion of Science.
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Akane Hayashi and Naoya Matsunaga contributed equally to this study.
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Hayashi, A., Matsunaga, N., Okazaki, H. et al. A Disruption Mechanism of the Molecular Clock in a MPTP Mouse Model of Parkinson’s Disease. Neuromol Med 15, 238–251 (2013). https://doi.org/10.1007/s12017-012-8214-x
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DOI: https://doi.org/10.1007/s12017-012-8214-x