Elucidation of the mechanism of mitochondrial maintenance by Parkinson's disease gene products

• Project/Area Number: 26461280
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Juntendo University
• Principal Investigator: SHIBA Kahori 順天堂大学, 医学(系)研究科(研究院), 准教授 (30468582)
• Co-Investigator(Renkei-kenkyūsha): IMAI Yuzuru 順天堂大学, 医学研究科, 先任准教授 (30321730) ; INOSHITA Tsuyoshi 順天堂大学, 医学研究科, 助教 (20601206)
• Research Collaborator: HATTORI Nobutaka 順天堂大学, 医学部, 教授 (80218510) ; AKAMATSU Wado 順天堂大学, 医学研究科, 特任教授 (60338184)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: Parkin / PINK1 / パーキンソン病 / マイトファジー / mitophagy / 遺伝性パーキンソン病

Outline of Final Research Achievements

The Parkinson’s disease gene products PINK1 and Parkin are involved in the maintenance of mitochondrial functions. It has been demonstrated that PINK1 activates Parkin through its phosphorylation, which leads to selective removal of damaged mitochondria.
This study uncovered that PINK1 and Parkin have a role to amplify the phospho-ubiquitin chains on the damaged mitochondria as their degradation signal. Moreover, the amplification system of the phospho-ubiquitin signal was compromised in dopaminergic neurons derived for patient’s iPS cells, which strongly suggests that the dysfunction of this system is involved in PD pathogenesis.

Research Products

• [Journal Article] Evidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson’s disease (2017)
  • Author(s): Shiba-Fukushima Kahori、Ishikawa Kei-Ichi、Inoshita Tsuyoshi、Izawa Nana、Takanashi Masashi、Sato Shigeto、Onodera Osamu、Akamatsu Wado、Okano Hideyuki、Imai Yuzuru、Hattori Nobutaka
  • Journal Title: Human Molecular Genetics Volume: 26 Pages: 3172-3185
  • DOI: 10.1093/hmg/ddx201
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin mitochondrial tethering. (2014)
  • Author(s): Shiba-Fukushima K, Arano T, Matsumoto G, Inoshita T, Yoshida S, Ishihama Y, Ryu KY, Nukina N, Hattori N, Imai Y.
  • Journal Title: PLoS Genet. Volume: 10 Issue: 12 Pages: 1004861-1004861
  • DOI: 10.1371/journal.pgen.1004861
  • Peer Reviewed / Open Access
• [Journal Article] Lysine 63-linked polyubiquitination is dispensable for Parkin-mediated mitophagy. (2014)
  • Author(s): Shiba-Fukushima K, Inoshita T, Hattori N, Imai Y.
  • Journal Title: J Biol Chem. Volume: 289 Issue: 48 Pages: 33131-6
  • DOI: 10.1074/jbc.c114.580944
  • Peer Reviewed / Open Access
• [Journal Article] PINK1-mediated phosphorylation of Parkin boosts Parkin activity in Drosophila. (2014)
  • Author(s): Shiba-Fukushima K, Inoshita T, Hattori N, Imai Y.
  • Journal Title: PLoS Genet. Volume: Jun 5;10(6) Issue: 6 Pages: 1004391-1004391
  • DOI: 10.1371/journal.pgen.1004391
  • Peer Reviewed / Open Access
• [Presentation] Evidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson’s disease. (2016)
  • Author(s): Shiba K, Ishikawa K, Inoshita T, Akamatsu W, Hideyuki O, Imai Y, Hattori N
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [Presentation] In vivo evidence for the involvement of phospho-ubiquitin signal. (2016)
  • Author(s): Shiba K, Ishikawa K, Takanashi M, Akamatsu W, Imai Y, Hattori N
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2016-07-22
• [Presentation] PINK1-Parkinシグナルによるミトコンドリアの品質管理機構 (2015)
  • Author(s): 柴 佳保里
  • Organizer: 第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-02
  • Invited
• [Presentation] Phosphorylation of Mitochondrial K63-Linked Polyubiquitin by PINK1 Promotes Parkin Mitochondrial Tethering (2015)
  • Author(s): 福嶋 佳保里
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 新潟コンベンションセンター
  • Year and Date: 2015-05-23
• [Presentation] Lysine 63-linked polyubiquitination is dispensable for Parkin-mediated mitophagy (2014)
  • Author(s): Shiba-Fukushima K, Inoshita T, Hattori N, Imai Y
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-11
• [Presentation] PINK1-Parkinミトコンドリア品質管理機構に関与する分子の探索 (2014)
  • Author(s): 柴 佳保里、井下 強、梅崎 勇次郎、今居 譲、服部 信孝
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡
  • Year and Date: 2014-05-23
• [Book] 実験医学 (2015)
  • Author(s): 今居 譲、柴佳保里、服部信孝
  • Total Pages: 134
  • Publisher: 羊土社