A disruption mechanism of the molecular clock in a MPTP mouse model of parkinson's disease

Akane Hayashi, Naoya Matsunaga, Hiroyuki Okazaki, Keisuke Kakimoto, Yoshinori Kimura, Hiroki Azuma, Eriko Ikeda, Takeshi Shiba, Mayumi Yamato, Ken Ichi Yamada, Satoru Koyanagi, Shigehiro Ohdo

研究成果: Contribution to journalArticle査読

29 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)238-251
ページ数14
ジャーナルNeuroMolecular Medicine
15
2
DOI
出版ステータス出版済み - 6 2013

All Science Journal Classification (ASJC) codes

  • 分子医療
  • 神経学
  • 細胞および分子神経科学

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