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To elucidate the pathogenesis of Parkinson' s disease and to develop a new therapy for the disease

Research Project

Project/Area Number 20023028
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionJuntendo University

Principal Investigator

HATTORI Nobutaka  Juntendo University, 医学部, 教授 (80218510)

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)
久保 紳一郎  順天堂大学, 医学部, 准教授 (20327795)
Project Period (FY) 2008 – 2009
Project Status Completed (Fiscal Year 2009)
Budget Amount *help
¥39,000,000 (Direct Cost: ¥39,000,000)
Fiscal Year 2009: ¥19,600,000 (Direct Cost: ¥19,600,000)
Fiscal Year 2008: ¥19,400,000 (Direct Cost: ¥19,400,000)
KeywordsParkin / PINK1 / CCCP / ミトコンドリア / Mitophagy / 品質管理 / オートファジー / 蛋白分解系 / 遺伝性パーキンソン病 / 学習能力 / DJ-1 / 共通機構
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.

Report

(3 results)
  • 2009 Annual Research Report   Final Research Report ( PDF )
  • 2008 Annual Research Report
  • Research Products

    (22 results)

All 2010 2009 2008

All Journal Article (14 results) (of which Peer Reviewed: 6 results) Presentation (3 results) Book (3 results) Patent(Industrial Property Rights) (2 results)

  • [Journal Article] PINK1 is recruited to mitochondria with parkin and associates with LC3 in mitophagy.2010

    • Author(s)
      Kawajiri S, Saiki S, Sato S, Sato F, Hatano T, Eguchi H, Hattori N
    • Journal Title

      FEBS Lett 584(6)

      Pages: 1073-9

    • Related Report
      2009 Final Research Report
  • [Journal Article] Mutation analysis for DJ-1 in sporadic and familial parkinsonism: Screening strategy in parkinsonism.2009

    • Author(s)
      Tomiyama H, Li Y, Yoshino H, Mizuno Y, Kubo S, Toda T, Hattori N
    • Journal Title

      Neurosci Lett 455

      Pages: 159-161

    • Related Report
      2009 Final Research Report
  • [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
    • Journal Title

      Nat Genet 41

      Pages: 1303-1307

    • Related Report
      2009 Final Research Report
  • [Journal Article] Excitatory amino acid transporter 2 associates with phosphorylated tau and is localized in neurofibrillary tangles of tauopathic brains.2009

    • Author(s)
      Sasaki K, Shimura H, Itaya M, Tanaka R, Mori H, Mizuno Y, Kosik KS, Tanaka S, Hattori N
    • Journal Title

      FEBS Lett 583

      Pages: 2194-200

    • Related Report
      2009 Final Research Report
  • [Journal Article] Programmed cell death-2 isoforml is ubiquitinated by parkin and increased in the substantia nigra of patients with autosomal recessive Parkinson's disease.2009

    • Author(s)
      Fukae J, Sato S, Shiba K, Sato K, Mori H, Sharp PA, Mizuno Y, Hattori N
    • Journal Title

      FEBS Lett 583

      Pages: 521-525

    • Related Report
      2009 Final Research Report
  • [Journal Article] Parkin stabilizes PINK1 through direct interaction.2009

    • Author(s)
      Shiba K, Arai T, Sato S, Kubo S, Ohba Y, Mizuno Y, Hattori N
    • Journal Title

      Biochem Biophys Res Commun 383

      Pages: 331-335

    • Related Report
      2009 Final Research Report
  • [Journal Article] Screening PARK Genes for Mutations in Early Onset Parkinson's Disease Patients from Queensland, Australia2009

    • Author(s)
      Mellick GD, Siebert GA, Funayama M, Buchanan DD, Li Y, Imamichi Y, Yoshino H, Silburn PA, Hattori N
    • Journal Title

      Parkinsonism & Related Disorders 15

      Pages: 105-109

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A new mutation in the GCH1 gene presents as early-onset Parkinsonism2009

    • Author(s)
      Momma K, Funayama M, Li Y, Ichinose H, Motoyoshi K, Hattori N, Mizuno Y, Kamakura K
    • Journal Title

      Parkinsonism & Related Disorders 15

      Pages: 160-161

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Programmed cell death-2 isoform1 is ubiquitinated by parkin and increased in the substantia nigra of patients with autosomal recessive Parkinson's disease.2009

    • Author(s)
      Fukae J, Sato S, Shiba K, Sato K, Mori H, Sharp PA, Mizuno Y, Hattori N
    • Journal Title

      EEBS Lett 383

      Pages: 521-525

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [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
    • Journal Title

      Neurology 70

      Pages: 1491-1493

    • Related Report
      2009 Final Research Report
  • [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
    • Journal Title

      Arch Neurol 65

      Pages: 802-808

    • Related Report
      2009 Final Research Report
  • [Journal Article] Mutation analysis of the PINK1 gene in 391 patients with Parkinson disease. 2008 Jun ; 65(6) : 802-82008

    • Author(s)
      Kumazawa R, et.al.
    • Journal Title

      Arch Neurol 65

      Pages: 802-808

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Familial narkinsonism with dieenic narkin and PINK1 mutations2008

    • Author(s)
      Funayama M, et.al.
    • Journal Title

      Mov Disord 65

      Pages: 802-808

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] PARK9-linked parkinsonism in Eastern Asia : Mutation detection in ATP13A2 and clinical phenotype2008

    • Author(s)
      Nina YP, et.al.
    • Journal Title

      Neurology 70

      Pages: 1491-1493

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Presentation] Plenary Session III "Young onset PD"2009

    • Author(s)
      Hattori N
    • Organizer
      the 2nd Asian Oceanian Parkinson's Disease and Movement Disorders Congress
    • Place of Presentation
      New Delhi
    • Year and Date
      2009-02-16
    • Related Report
      2009 Final Research Report
  • [Presentation] Plenary Session III "Young onset PD".2009

    • Author(s)
      Hattori N
    • Organizer
      the 2nd Asian Oceanian Parkdnson's Disease and Movement Disorders Congress
    • Place of Presentation
      New Delhi
    • Year and Date
      2009-02-16
    • Related Report
      2009 Annual Research Report
  • [Presentation] Parkinson's disease in Asia2008

    • Author(s)
      Hattori N
    • Organizer
      Genetic Epidemiology of Parkinson's Disease 3rd Annual meeting
    • Place of Presentation
      Trondheim, Norway
    • Year and Date
      2008-06-09
    • Related Report
      2008 Annual Research Report
  • [Book] いきなり名医!パーキンソン病Q&A2009

    • Author(s)
      服部信孝
    • Total Pages
      145
    • Publisher
      日本医事新報社
    • Related Report
      2009 Final Research Report
  • [Book] いきなり名医!パーキンソン病Q&A.2009

    • Author(s)
      服部信孝
    • Total Pages
      145
    • Publisher
      日本医事新報社
    • Related Report
      2009 Annual Research Report
  • [Book] ここまでわかったパーキンソン病研究2008

    • Author(s)
      服部信孝
    • Total Pages
      466
    • Publisher
      医師薬出版
    • Related Report
      2008 Annual Research Report
  • [Patent(Industrial Property Rights)] パーキンソン病モデルマウス及びその作製方法並びに該マウスを用いたパーキンソン病治療薬のスクリーニング方法及び評価方法2010

    • Inventor(s)
      岩井一宏、坂田真一、服部信孝
    • Acquisition Date
      2010-03-18
    • Related Report
      2009 Final Research Report
  • [Patent(Industrial Property Rights)] 岩井一宏、坂田真一、服部信孝2009

    • Inventor(s)
      パーキンソン病モデルマウス及びその作製方法並びに該マウスを用いたパーキンソン病治療薬のスクリーニング方法及び評価方法
    • Acquisition Date
      2009-03-19
    • Related Report
      2009 Final Research Report

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Published: 2008-04-01   Modified: 2018-03-28  

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