2009 Fiscal Year Final Research Report
To elucidate the pathogenesis of Parkinson' s disease and to develop a new therapy for the disease
| Project/Area Number |
20023028
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Juntendo University |
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Principal Investigator |
HATTORI Nobutaka Juntendo University, 医学部, 教授 (80218510)
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| Co-Investigator(Kenkyū-buntansha) |
SATO Shigeto 順天堂大学, 医学部・神経学, 准教授 (00445537)
SHIOMO Yashushi 順天堂大学, 医学部・神経学, 准教授 (70286714)
HATANO Taku 順天堂大学, 医学部・神経学, 助教 (60338390)
FUNAYAMA Manabu 順天堂大学, 医学部・神経学, 助教 (70468578)
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| Project Period (FY) |
2008 – 2009
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| Keywords | Parkin / PINK1 / CCCP / ミトコンドリア / Mitophagy / 品質管理 |
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| Research Abstract |
Parkin and PINK1 has revealed that ubiquitylation and mitochondrial integrity are key factors in disease pathogenesis. In this study, we show that PINK1 is rapidly and constitutively degraded under steady-state conditions in a mitochondrial membrane potential-dependent manner and that a loss in mitochondrial membrane potential stabilizes PINK1 mitochondrial accumulation. Furthermore, PINK1 recruits Parkin from the cytoplasm to mitochondria with low membrane potential to initiate the autophagic degradation of damaged mitochondria. In addition, we analyzed the secretion system of insulin using beta-cells originated from parkin KO mice. We identified selective impairments of phase I of insulin secretion system. This finding could be available for elucidating the pathogenesis of neuronal cell death. Moreover, we analyzed the alteration of cellular localization of both wild and mutant types of ATP13A2 that is a causative gene for Park9. The wild type localized on the outer membrane of lysosome. In contrast, the mutants located in the endoplasmic reticulum. The difference of localization could induce the loss-of-function effects.
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[Journal Article] Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease.2009
Author(s)
Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, Kawaguchi T, Tsunoda T, Watanabe M, Takeda A, Tomiyama H, Nakashima K, Hasegawa K, Obata F, Yoshikawa T, Kawakami H, Sakoda S, Yamamoto M, Hattori N, Murata M, Nakamura Y, Toda T
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Journal Title
Nat Genet 41
Pages: 1303-1307
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[Journal Article] PARK9-linked parkinsonism in Eastern Asia: Mutation detection in ATP13A2 and clinical phenotype.2008
Author(s)
Ning Y, Kanai K, Tomiyama H, Li Y, Funayama M, Yoshino H, Sato S, Asahina M, Kuwabara S, Takeda A, Hattori T, Mizuno Y, Hattori N
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Journal Title
Neurology 70
Pages: 1491-1493
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[Journal Article] Mutation analysis of the PINK1 gene in 391 patients with Parkinson disease.2008
Author(s)
Kumazawa R, Tomiyama H, Li Y, Imamichi Y, Funayama M, Yoshino H, Yokochi F, Fukusako T, Takehisa Y, Kashihara K, Kondo T, Elibol B, Bostantjopoulou S, Toda T, Takahashi H, Yoshii F, Mizuno Y, Hattori N
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Journal Title
Arch Neurol 65
Pages: 802-808
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