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

• Project/Area Number: 20023028
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Juntendo 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: ¥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)
• Keywords: Parkin / 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.

Research Products

• [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
• [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
• [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
• [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
• [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
• [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
• [Journal Article] Screening PARK Genes for Mutations in Early Onset Parkinson's Disease Patients from Queensland, Australia (2009)
  • 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
  • Peer Reviewed
• [Journal Article] A new mutation in the GCH1 gene presents as early-onset Parkinsonism (2009)
  • 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
  • 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
  • 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
• [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
• [Journal Article] Mutation analysis of the PINK1 gene in 391 patients with Parkinson disease. 2008 Jun ; 65(6) : 802-8 (2008)
  • Author(s): Kumazawa R, et.al.
  • Journal Title: Arch Neurol 65 Pages: 802-808
  • Peer Reviewed
• [Journal Article] Familial narkinsonism with dieenic narkin and PINK1 mutations (2008)
  • Author(s): Funayama M, et.al.
  • Journal Title: Mov Disord 65 Pages: 802-808
  • Peer Reviewed
• [Journal Article] PARK9-linked parkinsonism in Eastern Asia : Mutation detection in ATP13A2 and clinical phenotype (2008)
  • Author(s): Nina YP, et.al.
  • Journal Title: Neurology 70 Pages: 1491-1493
  • 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
• [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
• [Presentation] Parkinson's disease in Asia (2008)
  • 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
• [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
• [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
• [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
• [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
• [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