Analysis of epigenetic modification in parkinson's disease patient-specific iPSCs-derived dopamine neurons

• Project/Area Number: 16K08280
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pharmacology in pharmacy
• Research Institution: Hoshi University
• Principal Investigator: Kuzumaki Naoko 星薬科大学, 薬学部, 准教授 (10507669)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: パーキンソン病 / iPS 細胞 / ドパミン神経 / エピジェネティクス / iPS 細胞 / 中脳ドパミン神経 / ヒト iPS 細胞 / 神経科学 / ドパミン

Outline of Final Research Achievements

In Parkinson's disease, it has been widely accepted that the continuous loss of dopamine (DA) neurons in the substantia nigra leads to movement disorders. However, the mechanism that underlies the selective loss of DA neurons in Parkinson's disease is not fully understood. In this study, we found a dramatic increase in catechol-O-methyltransferase (COMT) along with a decrease in DNA methylation levels in Parkinson’s disease-specific iPSC-derived DA neurons. Furthermore, in the cell-specific in vivo study, overexpression of COMT in DA neurons of the substantia nigra of dopamine transporter-Cre mice produced cataleptic behaviors accompanied by impaired motor coordination. These findings suggest that increase of COMT, with its epigenetic modification, in dopaminergic neurons may result in the dysfunction of synaptic DA transmission in the initial process of Parkinson's disease.

Academic Significance and Societal Importance of the Research Achievements

本研究において、疾患特異的 iPS 細胞技術や神経科学的アプローチに従って、黒質ドパミン神経におけるエピジェネティック修飾を伴った COMT の発現増加を見出し、こうしたドパミン神経特異的 COMT の発現増加は、ドパミン神経の機能障害に関与する可能性を明らかとした。このような結果は、パーキンソン病態の初期段階を反映していることが考えられるため、初期段階における治療法の開発の一助となる可能性が示唆された。

Research Products

• [Journal Article] Cell-specific overexpression of COMT in dopaminergic neurons of Parkinson’s disease (2019)
  • Author(s): Naoko Kuzumaki, Yukari Suda, Chizuru Iwasawa, Michiko Narita, Takefumi Sone, Moe Watanabe, Aya Maekawa, Takuya Matsumoto, Wado Akamatsu, Katsuhide Igarashi, Hideki Tamura, Hideyuki Takeshima, Vivianne L. Tawfik, Toshikazu Ushijima, Nobutaka Hattori, Hideyuki Okano and Minoru Narita
  • Journal Title: Brain Volume: 印刷中
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Down-regulation of ghrelin receptors on dopaminergic neurons in the substantia nigra contributes to Parkinson's disease-like motor dysfunction. (2018)
  • Author(s): Suda Y, Kuzumaki N, Sone T, Narita M, Tanaka K, Hamada Y, Iwasawa C, Shibasaki M, Maekawa A, Matsuo M, Akamatsu W, Hattori N, Okano H, Narita M.
  • Journal Title: Mol Brain. Volume: 11 Issue: 1 Pages: 6-6
  • DOI: 10.1186/s13041-018-0349-8
  • Peer Reviewed / Open Access
• [Journal Article] Effect of ghrelin on the motor deficit caused by the ablation of nigrostriatal dopaminergic cells or the inhibition of striatal dopamine receptors. (2018)
  • Author(s): Suda Y, Kuzumaki N, Narita M, Hamada Y, Shibasaki M, Tanaka K, Tamura H, Kawamura T, Kondo T, Yamanaka A, Narita M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 496 Issue: 4 Pages: 1102-1108
  • DOI: 10.1016/j.bbrc.2018.01.145
  • Peer Reviewed
• [Journal Article] Parkin absence accelerates microtubule aging in dopaminergic neurons (2018)
  • Author(s): Cartelli D, Amadeo A, Calogero AM, Casagrande FVM, De Gregorio C, Gioria M, Kuzumaki N, Costa I, Sassone J, Ciammola A, Hattori N, Okano H, Goldwurm S, Roybon L, Pezzoli G, Cappelletti G
  • Journal Title: Neurobiology of Aging Volume: 61 Pages: 66-74
  • DOI: 10.1016/j.neurobiolaging.2017.09.010
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Efficient induction of dopaminergic neuron differentiation from induced pluripotent stem cells reveals impaired mitophagy in PARK2 neurons. (2017)
  • Author(s): Suzuki S, Akamatsu W, Kisa F, Sone T, Ishikawa KI, Kuzumaki N, Katayama H, Miyawaki A, Hattori N, Okano H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 489 Issue: 1 Pages: 88-93
  • DOI: 10.1016/j.bbrc.2016.12.188
  • Peer Reviewed / Open Access
• [Journal Article] Functional Neurons Generated from T Cell-Derived Induced Pluripotent Stem Cells (2016)
  • Author(s): Matsumoto T, Fujimori K, Andoh-Noda T, Ando T, Kuzumaki N, Toyoshima M, Tada H, Imaizumi K, Ishikawa M, Yamaguchi R, Isoda M, Zhou Z, Sato S, Kobayashi T, Ohtaka M, Nishimura K, Kurosawa H, Yoshikawa T, Takahashi T, Nakanishi M, Ohyama M, Hattori N, Akamatsu W, Okano H.
  • Journal Title: Stem Cell Reports. Volume: 6 Issue: 3 Pages: 422-35
  • DOI: 10.1016/j.stemcr.2016.01.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] ヒト疾患特異的 iPS 細胞技術を応用した難治性神経疾患のメカニズム解析 (2017)
  • Author(s): 葛巻 直子, 須田雪明, 成田道子, 岡野栄之, 成田 年
  • Organizer: 第90回 日本薬理学会年会
  • Place of Presentation: 長崎
  • Year and Date: 2017-03-15
• [Presentation] ヒト疾患特異的 iPS 細胞研究の最前線とリバーストランスレーショナルリサーチへの応用 (2017)
  • Author(s): 葛巻 直子, 須田雪明, 岩澤千鶴, 成田道子,岡野栄之, 成田年
  • Organizer: 第136回日本薬理学会関東部会
• [Presentation] Analysis of epigenetic changes in the pathology of Parkinson's disease using PARK2 patient-specific iPS cells (2017)
  • Author(s): Suda Y, Kuzumaki N, Akamatsu S, Ishimi H, Iwasawa C, Narita M, Tamura H, Maekawa A, Sone T, Igarashi K, Takeshima H, Ushijima T, Hattori N, Okano H, Narita M.
  • Organizer: 第40回日本神経科学大会
• [Presentation] ヒト疾患特異的iPS細胞を用いた神経・精神疾患メカニズムの解明に向けた多角的解析 (2017)
  • Author(s): 葛巻 直子, 須田雪明, 岩澤千鶴, 成田年
  • Organizer: 第61回日本薬学会 関東支部大会
• [Presentation] パーキンソン病患者iPS 細胞由来神経細胞内の代謝変動解析 (2017)
  • Author(s): 葛巻 直子, 須田雪明, 岩澤千鶴, 成田年
  • Organizer: 第47回日本神経精神薬理学会年会
• [Presentation] Analysis of dopaminergic dysfunction-related molecules in the developmental stage of Parkinson's disease using human disease-specific iPS cells (2017)
  • Author(s): 葛巻 直子, 須田雪明, 岩澤千鶴, 成田道子, 渡邉 萌, 田村 英紀, 五十嵐 勝秀, 牛島 俊和, 服部 信孝,岡野栄之, 成田年
  • Organizer: 第40回日本分子生物学会年会
• [Presentation] Hypomethylation of COMT gene promoter in Parkinson’s disease-specific iPS cell-derived dopaminergic neurons (2016)
  • Author(s): Y. Suda，N. Kuzumaki，M. Narita，K. Igarashi，H. Takeshima，T. Ushijima，N. Hattori，H. Okano，M. Narita
  • Organizer: 第 39回日本神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2016-07-20
• [Presentation] Multiple analysis for the DNA methylation changed in parkinson's disease specific iPSC-derived dopaminergic neurons (2016)
  • Author(s): N. Kuzumaki, Y. Suda, K. Igarashi, M. Narita, H. Takeshima, T. Ushijima, N. Hattori, M. Suematsu, H. Okano, M. Narita
  • Organizer: ISSCR 2016 Annual meeting
  • Place of Presentation: サンフランシスコ
  • Year and Date: 2016-06-22
  • Int'l Joint Research
• [Presentation] Analysis of changes in the expression of dopamine-related genes with epigenetic chenges in parkinson's disease-specific iPS cell-derived dopaminergic neurons (2016)
  • Author(s): Y. Suda, N. Kuzumaki, M. Narita, K. Igarashi, H. Takeshima, T. Ushijima, N. Hattori, H. Okano, M. Narita
  • Organizer: ISSCR 2016 Annual meeting
  • Place of Presentation: サンフランシスコ
  • Year and Date: 2016-06-22
  • Int'l Joint Research
• [Presentation] ヒト疾患特異的 iPS 細胞を用いたパーキンソン病態下におけるエピゲノム変化の解析 (2016)
  • Author(s): 須田雪明, 葛巻直子, 成田道子, 五十嵐勝秀, 竹島秀幸, 服部信孝, 岡野栄之, 牛島俊和, 成田 年
  • Organizer: 第10回日本エピジェネティクス研究会年会
  • Place of Presentation: 大阪
  • Year and Date: 2016-05-19