Elucidation of the mechanism of Parkinson's disease iPS cell-derived dopaminergic nerurons due to aging

• Project/Area Number: 18K15463
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Juntendo University
• Principal Investigator: Ishikawa Kei-ichi 順天堂大学, 医学(系)研究科(研究院), 助教 (90733973)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: パーキンソン病 / iPS細胞 / 薬剤スクリーニング / 老化 / αシヌクレイン / 細胞老化 / ドーパミン神経細胞 / アルファシヌクレイン

Outline of Final Research Achievements

The dopaminergic neurons differentiated from iPS cells derived from hereditary Parkinson's disease (PD) patients (PARK2/4/6/9/22) were represented the pathological mechanism of PD such as their vulnerability, mitochondrial abnormality, abnormality of autophagy, α-synuclein accumulation. Four kinds of candidate compounds were identified by compound screening in PARK2/6-iPS cell-derived dopamine neurons. Furthermore, we reported that some dopaminergic neurons derived from sporadic PD-iPS cells also showed some common pathomechanisms and drug responsiveness with hereditary PD-iPS cells. We also analyzed the mechanism of senescence-promoting compounds in neuronal senescence, and reproduced the accumulation of α-synuclein in PARK4-iPS cell-derived neurons, which was difficult to reproduce in a short-term culture. This result indicates the relationship between senescence and PD pathology.

Academic Significance and Societal Importance of the Research Achievements

遺伝性パーキンソン病患者iPS細胞を用いて、患者神経における老化を含めた複数の病態機序を示すことができた。薬剤スクリーニングシステムを確立したこと、本システムにより治療候補化合物を見いだし、さらに孤発性パーキンソン病患者由来細胞でも一部は遺伝性と共通の異常を呈すること、さらに遺伝性パーキンソン病のスクリーニングから得られた治療候補化合物に同様の効果があることを示したことは、今後の新たな治療薬開発に繋がる成果である。

Research Products

• [Journal Article] Variants in saposin D domain of prosaposin gene linked to Parkinson’s disease (2020)
  • Author(s): Oji Y, Hatano T, Ueno SI, Funayama M, Ishikawa KI, Okuzumi A, Noda S, Sato S, Satake W, Toda T, Li Y, Hino-Takai T, Kakuta S, Tsunemi T, Yoshino H, Nishioka K, Hattori T, Mizutani Y, Mutoh T, Yokochi F, et al.
  • Journal Title: Brain Volume: 143 Issue: 4 Pages: 1190-1205
  • DOI: 10.1093/brain/awaa064
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] BRUP-1, an intracellular bilirubin modulator, exerts neuroprotective activity in a cellular Parkinson’s disease model. (2020)
  • Author(s): Kataura, T., Saiki, S., Ishikawa, K., Akamatsu, W., Sasazawa, Y., Hattori, N., Imoto, M.
  • Journal Title: J. Neurochemstry Volume: - Issue: 1 Pages: 81-97
  • DOI: 10.1111/jnc.14997
  • Peer Reviewed / Open Access
• [Journal Article] Mutations in CHCHD2 cause α-synuclein aggregation (2019)
  • Author(s): Ikeda A., Nishioka K., Meng H., Takanashi M., Hasegawa I., Inoshita T., Shiba-Fukushima K., Li Y., Yoshino H., Mori A., Okuzumi A., Yamaguchi A., Nonaka R., Izawa N., Ishikawa K.I., Saiki H., Morita M., Hasegawa M., Hasegawa K., Elahi M., et al.
  • Journal Title: Human Molecular Genetics Volume: 28 Issue: 23 Pages: 3895-3911
  • DOI: 10.1093/hmg/ddz241
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Plasma metabolite biomarkers for multiple system atrophy and progressive supranuclear palsy (2019)
  • Author(s): Mori Akio、Ishikawa Kei-Ichi、Saiki Shinji、Hatano Taku、Oji Yutaka、Okuzumi Ayami、Fujimaki Motoki、Koinuma Takahiro、Ueno Shin-Ichi、Imamichi Yoko、Hattori Nobutaka
  • Journal Title: PLOS ONE Volume: 14 Issue: 9 Pages: e0223113-e0223113
  • DOI: 10.1371/journal.pone.0223113
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neuroprotective effects of memantine via enhancement of autophagy (2019)
  • Author(s): Hirano Kazuoki、Fujimaki Motoki、Sasazawa Yukiko、Yamaguchi Akihiro、Ishikawa Kei-Ichi、Miyamoto Kengo、Souma Sanae、Furuya Norihiko、Imamichi Yoko、Yamada Daisuke、Saya Hideyuki、Akamatsu Wado、Saiki Shinji、Hattori Nobutaka
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 518 Issue: 1 Pages: 161-170
  • DOI: 10.1016/j.bbrc.2019.08.025
  • Peer Reviewed / Open Access
• [Journal Article] Multi-year whole-blood transcriptome data for the study of onset and progression of Parkinson's Disease. (2019)
  • Author(s): Valentine MNZ, Hashimoto K, Fukuhara T, Saiki S, Ishikawa KI, Hattori N, Carninci P.
  • Journal Title: Sci Data Volume: 6 Issue: 1 Pages: 1-7
  • DOI: 10.1038/s41597-019-0022-9
  • Peer Reviewed / Open Access
• [Journal Article] p150glued deficiency impairs effective fusion between autophagosomes and lysosomes due to their redistribution to the cell periphery. (2019)
  • Author(s): Ishikawa-KI, Saiki S, Furuya N, Imamichi Y, Tsuboi Y, Hattori N
  • Journal Title: Neuroscience Letters Volume: 690 Pages: 181-187
  • DOI: 10.1016/j.neulet.2018.10.036
  • Peer Reviewed / Open Access
• [Journal Article] Soluble epoxide hydrolase plays a key role in the pathogenesis of Parkinson’s disease (2018)
  • Author(s): Ren Qian、Ma Min、Yang Jun、Nonaka Risa、Yamaguchi Akihiro、Ishikawa Kei-ichi、Kobayashi Kenta、Murayama Shigeo、Hwang Sung Hee、Saiki Shinji、Akamatsu Wado、Hattori Nobutaka、Hammock Bruce D.、Hashimoto Kenji
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 115 Issue: 25
  • DOI: 10.1073/pnas.1802179115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Zonisamide Administration Improves Fatty Acid β-Oxidation in Parkinson's Disease. (2018)
  • Author(s): Ueno SI, Saiki S, Fujimaki M, Takeshige-Amano H, Hatano T, Oyama G, Ishikawa KI, Yamguchi A, Nojiri S, Akamatsu W, Hattori N.
  • Journal Title: Cells Volume: 8 Issue: 1 Pages: 14-14
  • DOI: 10.3390/cells8010014
  • Peer Reviewed / Open Access
• [Presentation] iPSC-based disease modeling for late onset neurodegenerative diseases using a chemical compound accelerating senescence. (2019)
  • Author(s): Takahiro Shiga, Sakura Miyoshi, Naoko Kuzumaki, Ke-ichi Ishikawa, Nobutaka Hattori, Hideyuki Okano, Wado Akamatsu
  • Organizer: International Society for Stem Cell Research (ISSCR) 2019
  • Int'l Joint Research
• [Presentation] iPSC-based drug screening for PARK9, a familial Parkinson’s disease with impaired autophagy (2019)
  • Author(s): Kei-ichi Tsukiboshi, Akihiro Yamaguchi, Kei-ichi Ishikawa, Kazuaki Kanai, Hideyuki Okano, Nobutala Hattori, Wado Akamatsu
  • Organizer: International Society for Stem Cell Research (ISSCR) 2019
  • Int'l Joint Research
• [Presentation] Identification of potential therapeutic agents for impaired mitophagy in Parkinson’s disease (2019)
  • Author(s): Akihiro Yamaguchi, Kei-ichi Ishikawa, Tsuyoshi Inoshita, Kahori Shiba-Fukushima, Yuzuru Imai, Hideyuki Okano, Nobutaka Hattori, Wado Akamatsu
  • Organizer: International Society for Stem Cell Research (ISSCR) 2019
  • Int'l Joint Research
• [Presentation] ゾニサミドはパーキンソン病患者において脂肪酸β酸化を改善する (2019)
  • Author(s): 上野真一, 斉木臣二, 藤巻基紀, 竹重遥香, 波田野琢, 大山彦光, 石川景一, 山口昂大, 野尻宗子, 赤松和土, 服部信孝
  • Organizer: 第13回日本パーキンソン病・運動障害疾患学会
• [Presentation] フィーダーフリー培養系iPS細胞を用いた中脳特異ドパミン作動性ニューロンの分化誘導法の検討 (2019)
  • Author(s): 野中里紗、石川景一、志賀孝宏、中村亮太、城崇之、大山彦光、服部信孝、赤松和土
  • Organizer: 第18回日本再生医療学会総会
• [Presentation] パーキンソン病iPS細胞を用いた病態解明・創薬スクリーニング (2019)
  • Author(s): 山口昂大, 石川景一, 斉木臣二, 船山学, 金井数明, 岡野栄之, 服部信孝, 赤松和土
  • Organizer: 第18回日本再生医療学会総会
• [Presentation] 老化を加速する低分子化合物を用いた神経変性疾患iPS解析システムの構築 (2019)
  • Author(s): 志賀孝宏, 三好さくら, 葛巻直子, 石川景一, 服部信孝, 岡野栄之, 赤松和土
  • Organizer: 第18回日本再生医療学会総会
• [Presentation] フィーダーフリー培養系iPS細胞を用いた中脳特異ドパミン作動性ニューロンの分化誘導法の検討 (2018)
  • Author(s): 野中里紗、石川景一、志賀孝宏、城崇之、中村亮太、大山彦光、斉木臣二、岡野栄之、服部信孝、赤松和土
  • Organizer: 第41回日本神経科学大会
• [Presentation] 老化を加速する低分子化合物を用いた神経変性疾患iPS解析システムの構築 (2018)
  • Author(s): 志賀孝宏, 三好さくら, 葛巻直子, 石川景一, 服部信孝, 岡野栄之, 赤松和土
  • Organizer: 第41回日本神経科学大会
• [Presentation] ATM阻害はヒトiPS細胞由来神経細胞の老化を加速させる (2018)
  • Author(s): 志賀孝宏, 三好さくら, 葛巻直子, 石川景一, 服部信孝, 岡野栄之, 赤松和土
  • Organizer: 第41回日本分子生物学会
• [Remarks]
  • URL: https://www.juntendo.ac.jp/graduate/genome/info_index.html