A Disruption Mechanism of the Molecular Clock in a MPTP Mouse Model of Parkinson’s Disease
| Autor: | Mayumi Yamato, Naoya Matsunaga, Akane Hayashi, Keisuke Kakimoto, Takeshi Shiba, Hiroyuki Okazaki, Eriko Ikeda, Shigehiro Ohdo, Ken Ichi Yamada, Yoshinori Kimura, Hiroki Azuma, Satoru Koyanagi |
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| Rok vydání: | 2013 |
| Předmět: |
Male
medicine.medical_specialty Circadian clock Substantia nigra AMP-Activated Protein Kinases Motor Activity Biology Chronobiology Disorders Body Temperature Mice Neuroblastoma Cellular and Molecular Neuroscience chemistry.chemical_compound Adenosine Triphosphate Catalytic Domain Cell Line Tumor Internal medicine medicine Animals Humans Circadian rhythm Phosphorylation Dose-Response Relationship Drug MPTP Dopaminergic Neurodegeneration ARNTL Transcription Factors MPTP Poisoning AMPK medicine.disease Cryptochromes Mice Inbred C57BL Neostriatum CLOCK Pyrimidines Endocrinology Gene Expression Regulation nervous system Neurology chemistry 1-Methyl-4-phenyl-1 2 3 6-tetrahydropyridine Nuclear Receptor Subfamily 1 Group D Member 1 Pyrazoles Molecular Medicine Protein Processing Post-Translational |
| Zdroj: | NeuroMolecular Medicine. 15:238-251 |
| ISSN: | 1559-1174 1535-1084 |
| DOI: | 10.1007/s12017-012-8214-x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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