Pathological analysis of hereditary Parkinson's disease using induced pluripotent stem cells

• Project/Area Number: 15K06777
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Kitasato University
• Principal Investigator: OHTA ETSURO 北里大学, 医療衛生学部, 講師 (60508042)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); 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)
• Keywords: パーキンソン病 / LRRK2 / iPS細胞 / TAU / ゲノム編集 / PARK8 / 神経変性

Outline of Final Research Achievements

LRRK2 is the causative molecule of the autosomal dominant hereditary form of Parkinson’s disease (PD), PARK8, which was originally defined in a study of a Japanese family harboring the I2020T mutation. In the present study, to elucidate the mechanism of neurodegeneration in PD caused by LRRK2, we generated iPS cells (iPSC) derived from fibroblasts of PD patients. We found that patient LRRK2 iPSC-derived neurons released less dopamine than control-iPSC-derived neurons. Furthermore, we demonstrated that patient iPSC-derived neurons had a lower phospho-AKT level than control-iPSC-derived neurons, and that the former showed an increased incidence of apoptosis relative to the controls. Interestingly, patient iPSC-derived neurons exhibited activation of GSK-3β and high Tau phosphorylation. In addition, the postmortem brain of the patient from whom the iPSC had been established exhibited deposition of neurofibrillary tangles as well as increased Tau phosphorylation in neurons.

Research Products

• [Int'l Joint Research] セントルイス・ワシントン大学(米国)
• [Journal Article] Establishment of DYT5 patient-specific induced pluripotent stem cells with a GCH1 mutation (2017)
  • Author(s): Murakami Nagahisa、Ishikawa Taizo、Kondo Takayuki、Imamura Keiko、Tsukita Kayoko、Enami Takako、Funayama Misato、Shibukawa Ran、Matsumoto Shinichi、Izumi Yuishin、Ohta Etsuro、Obata Fumiya、Kaji Ryuji、Inoue Haruhisa
  • Journal Title: Stem Cell Research Volume: 24 Pages: 36-39
  • DOI: 10.1016/j.scr.2017.07.029
  • NAID: 120006826719
  • Peer Reviewed
• [Journal Article] Leucine-rich repeat kinase 2 is a regulator of B cell function, affecting homeostasis, BCR signaling, IgA production, and TI antigen responses. (2016)
  • Author(s): Kubo M, Nagashima R, Ohta E, Maekawa T, Isobe Y, Kurihara M, Eshima K, Iwabuchi K, Sasaoka T, Azuma S, Melrose HL, Farrer MJ, Obata F
  • Journal Title: Journal of Neuroimmunology Volume: 292 Pages: 1-8
  • DOI: 10.1016/j.jneuroim.2016.01.005
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] I2020T mutant LRRK2 iPSC-derived neurons in the Sagamihara family exhibit increased Tau phosphorylation through the AKT/GSK-3β signaling pathway (2015)
  • Author(s): Ohta E, Nihira T, Uchino A, Imaizumi Y, Okada Y, Akamatsu W, Takahashi K, Hayakawa H, Nagai M, Ohyama M, Ryo M, Ogino M, Murayama S, Takashima A, Nishiyama K, Mizuno Y, Mochizuki H, Obata F, Okano H
  • Journal Title: Human Molecular Genetics Volume: 24(17) Issue: 17 Pages: 4879-4900
  • DOI: 10.1093/hmg/ddv212
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 遺伝性パーキンソン病患者iPS細胞由来神経細胞における経時的なmRNA発現解析 (2018)
  • Author(s): 太田悦朗、曽根岳史、大日方友理、鵜飼 英樹、久松知子、北川季子、石川充、駒野肇、上田泰己、小幡文弥、川村俊彦、岡野栄之
  • Organizer: 第17回日本再生医療学会総会
• [Presentation] 遺伝性パーキンソン病患者iPS細胞由来神経幹細胞移植マウスの作製および病態解析 (2018)
  • Author(s): 大日方友理、岩下 由佳、永井 真貴子、服部 精人、江島 耕二、小幡 文弥、川村 俊彦、岡野 栄之、太田悦朗
  • Organizer: 第17回日本再生医療学会総会
• [Presentation] Generation of gene-corrected iPSC from patient-derived iPSC with familial Parkinson's disease. (2017)
  • Author(s): Ohta E, Sone T, Obinata Y, Ukai H, Hisamatsu T, Kitagawa T, Ishikawa M, Komano H, Ueda HR, Obata F, Okano H
  • Organizer: International Society for Stem Cell Research 2017 Annual Meeting
  • Int'l Joint Research
• [Presentation] Generation of a mouse model of familial Parkinson’s disease bearing patient iPSC-derived transplanted neurospheres (2017)
  • Author(s): Obinata Y, Iwashita Y, Nagai M, Hattori A, Eshima K, Obata F, Okano H, Ohta E
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] Generation of a mouse model of familial Parkinson’s disease bearing patient iPSC-derived transplanted neurospheres (2017)
  • Author(s): Ohta E, Obinata Y, Iwashita Y, Nagai M, Hattori A, Eshima K, Obata F, Okano H
  • Organizer: Generation of a mouse model of familial Parkinson’s disease bearing patient iPSC-derived transplanted neurospheres
  • Int'l Joint Research
• [Presentation] 遺伝性パーキンソン病患者由来iPS細胞におけるゲノム編集iPS細胞の樹立 (2017)
  • Author(s): 太田悦朗、曽根岳史、大日方友理、鵜飼英樹、久松知子、北川季子、石川充、駒野肇、上田泰己、小幡文弥、岡野栄之
  • Organizer: 第16回日本再生医療学会総会
• [Presentation] 遺伝性パーキンソン病患者iPS細胞由来神経幹細胞移植マウスの作製 (2017)
  • Author(s): 大日方友理、岩下由佳、永井真貴子、服部精人、江島耕二、岡野栄之、小幡 文弥、太田悦朗
  • Organizer: 第40回日本神経科学大会
• [Presentation] Leucine-rich repeat kinase 2 is a regulator of B cell function, affecting homeostasis, BCR signaling, IgA production, and TI antigen responses (2016)
  • Author(s): KUBO M, OHTA E, ESHIMA K, IWABUCHI K, OBATA F
  • Organizer: 第45回日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター、ラグナガーデンホテル（沖縄県宜野湾市）
  • Year and Date: 2016-12-05
• [Presentation] 遺伝性パーキンソン病患者由来iPS細胞のゲノム編集および病態解析 (2016)
  • Author(s): 大日方友理、太田悦朗、曽根岳史、鵜飼英樹、久松知子、石川充、駒野肇、上田泰己、小幡文弥、岡野栄之
  • Organizer: 第11回日本臨床検査学教育学会学術大会
  • Place of Presentation: 神戸常盤大学（兵庫県神戸市）
  • Year and Date: 2016-08-31
• [Presentation] 遺伝性パーキンソン病患者由来iPS細胞におけるゲノム編集iPS細胞の樹立 (2016)
  • Author(s): 太田悦朗、曽根岳史、大日方友理、鵜飼英樹、久松知子、北川季子、石川充、駒野肇、上田泰己、小幡文弥、岡野栄之
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-07-20
• [Presentation] Segawa disease with action retrocollis (cervical dystonia); A case report of 23-year-old female (2016)
  • Author(s): Hoshino K, Hayashi M, Isono Y, Nagao Y, Kimura K, Hachimori K, Nozaki H, Ohta E, Obata F, Kawarai T, Kaji K
  • Organizer: International Child Neurology Congress (ICNC2016)
  • Place of Presentation: Amsterdam RAI Convention Centre(Netherland,Amsterdam)
  • Year and Date: 2016-05-04
  • Int'l Joint Research
• [Presentation] I2020T mutant LRRK2 iPSC-derived neurons exhibit increased Tau phosphorylation (2016)
  • Author(s): 太田悦朗、仁平友子、内野彰子、今泉陽一、岡田 洋平、赤松和土、高橋加代子、永井真貴子、大山学、梁正淵、荻野美恵子、村山繁雄、高島明彦、西山和利、 水野美邦、望月秀樹、小幡文弥、岡野栄之
  • Organizer: 第15回日本再生医療学会総会
  • Place of Presentation: 大阪府大阪市（大阪国際会議場）
  • Year and Date: 2016-03-17
• [Presentation] I2020T mutant LRRK2 iPSC-derived neurons in the Sagamihara family exhibit increased Tau phosphorylation through the AKT/GSK-3β signaling pathway (2015)
  • Author(s): Ohta E, Nihira T, Uchino A, Imaizumi Y, Okada Y, Akamatsu W, Takahashi K, Hayakawa H, Nagai M, Ohyama M, Ryo M, Ogino M, Murayama S, Takashima A, Nishiyama K, Mizuno Y, Mochizuki H, Obata F, Okano H
  • Organizer: XXI WFN World Congress on Parkinson's Disease and Related Disorders
  • Place of Presentation: Italy (Milan), Milano Congressi
  • Year and Date: 2015-12-09
  • Int'l Joint Research
• [Presentation] ゲノム編集した患者由来疾患iPS細胞の全ゲノム解析によって明らかになったこと (2015)
  • Author(s): 曽根岳史、朴聖俊、田中泰圭、太田 悦朗、日暮 憲道、中井 謙太、廣瀬 伸一、岡野 栄之
  • Organizer: BMB2015 (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: 兵庫県神戸市（神戸国際会議場）
  • Year and Date: 2015-12-01
• [Presentation] TALEN-mediated genome editing of patient-derived iPSCs for disease model studies (2015)
  • Author(s): Sone T, Tanaka Y, Ohta E, Hosoya M, Ichiyanagi N, Akiyama T, Higurashi N、Hirose S, Okano H
  • Organizer: The Conference on Transposition and Genome Engineering
  • Place of Presentation: Japan (Nara), Nara Kasugano International Forum IRAKA
  • Year and Date: 2015-11-17
  • Int'l Joint Research
• [Presentation] I2020T LRRK2変異をもつ遺伝性パーキンソン病患者のiPS細胞由来神経細胞はTauのリン酸化亢進を示す (2015)
  • Author(s): 太田悦朗、仁平友子、内野彰子、今泉陽一、岡田 洋平、赤松和土、高橋加代子、永井真貴子、大山学、梁正淵、荻野美恵子、村山繁雄、高島明彦、西山和利、 水野美邦、望月秀樹、小幡文弥、岡野栄之
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 兵庫県神戸市（神戸国際会議場）
  • Year and Date: 2015-07-28
• [Presentation] I2020T LRRK2 iPSC-derived neurons exhibit increased Tau phosphorylation (2015)
  • Author(s): 太田悦朗、仁平友子、内野彰子、今泉陽一、赤松和土、高橋加代子、永井真貴子、大山学、梁正淵、荻野美恵子、村山繁雄、高島明彦、西山和利、 水野美邦、望月秀樹、小幡文弥、岡野栄之
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 新潟県新潟市（朱鷺メッセ）
  • Year and Date: 2015-05-20
• [Book] 「週刊 医学のあゆみパーキンソン病の新展開－発症の分子機構と新規治療」 (2017)
  • Author(s): 高橋良輔（企画）、太田悦朗（分担執筆）
  • Total Pages: 116
  • Publisher: 医歯薬出版株式会社
• [Book] 月刊 細胞The CELL特集 疾患特異的iPS細胞を用いた病態解明の最前線 (2015)
  • Author(s): 太田悦朗、岡野栄之
  • Total Pages: 52
  • Publisher: ニューサイエンス社
• [Book] ブレインサイエンス・レビュー2015 (2015)
  • Author(s): 太田悦朗
  • Total Pages: 252
  • Publisher: 株式会社クバプロ
• [Remarks] 遺伝性パーキンソン病患者のｉＰＳ、「ゲノム編集」で正常な神経細胞に修復
  • URL: https://yomidr.yomiuri.co.jp/article/20170403-OYTET50009/?catname=news-kaisetsu_news
• [Remarks] プレスリリース全文
• [Remarks] 遺伝性パーキンソン病患者由来のiPS細胞を樹立
  • URL: http://www.nikkan.co.jp/news/nkx1020150618eaaz.html
• [Remarks] 慶大など、パーキンソン病患者由来のiPS細胞を樹立 - 脳内の病態を解明
  • URL: http://news.mynavi.jp/news/2015/06/17/298/