title: A disruption mechanism of the molecular clock in a MPTP mouse model of Parkinson's disease.
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.
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1, Maidashi, Fukuoka, Higashi-ku, 812-8582, Japan.
authors.forename: Akane
authors.initials: A
authors.lastname: Hayashi
authors.forename: Naoya
authors.initials: N
authors.lastname: Matsunaga
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okazaki
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kakimoto
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kimura
authors.forename: Hiroki
authors.initials: H
authors.lastname: Azuma
authors.forename: Eriko
authors.initials: E
authors.lastname: Ikeda
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shiba
authors.forename: Mayumi
authors.initials: M
authors.lastname: Yamato
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Yamada
authors.forename: Satoru
authors.initials: S
authors.lastname: Koyanagi
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ohdo
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors; D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors; D056930:ARNTL Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D000255:Adenosine Triphosphate / Q000627:therapeutic use; D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D020134:Catalytic Domain / Q000187:drug effects; D045744:Cell Line, Tumor; D021081:Chronobiology Disorders / Q000139:chemically induced* / Q000235:genetics; D056931:Cryptochromes / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020267:MPTP Poisoning / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D017072:Neostriatum / Q000187:drug effects / Q000502:physiology; D009447:Neuroblastoma / Q000473:pathology; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; C538963:CRY1 protein, human; D056931:Cryptochromes; C064353:NR1D1 protein, human; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D011720:Pyrazoles; D011743:Pyrimidines; C516138:dorsomorphin; D000255:Adenosine Triphosphate; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D055372:AMP-Activated Protein Kinases