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Elucidation of amyloid formation mechanism in Spinocerebellar ataxia and its application to drug therapy

Research Project

Project/Area Number 17H04032
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General pharmacology
Research InstitutionKobe University

Principal Investigator

SAITO NAOAKI  神戸大学, バイオシグナル総合研究センター, 教授 (60178499)

Co-Investigator(Kenkyū-buntansha) 足立 直子  神戸大学, バイオシグナル総合研究センター, 助教 (70604510)
上山 健彦  神戸大学, バイオシグナル総合研究センター, 准教授 (80346254)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2019: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2018: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2017: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Keywordsリン酸化酵素 / アミロイド / 創薬 / Hspファミリー / モデル動物
Outline of Final Research Achievements

Neurodegenerative disease that affects cerebellar Purkinje cells, is characterized by the intracellular formation of neurotoxic amyloid-like aggregates of genetic variants of protein kinase Cgamma (PKCgamma). We studied the effect of Hsp90 inhibitors, such as celastrol and Hsp990, for the PKCgamma aggregation by up-regelation of Hsp70 to develop a new drug for various neurodegenerative diseases.
Hsp990, a BBB permeable Hsp90 inhibitor, diminished net PKCgamma aggregation by preventing aggregate formation, resulting in decreased levels of apoptotic cell death among primary cultured Purkinje cells expressing PKCgamma variant. Furthermore, oral administration of Hsp990 decreased PKCgamma aggregation in SCA14 model mice. These compounds may be of utility as therapeutic agents against SCA14.

Academic Significance and Societal Importance of the Research Achievements

神経変性症の多くは神経内に凝集体を形成することを原因としていることが知られている。これらの凝集体の形成を抑制することができれば、多くの神経変性症治療薬の開発につながると考えられる。本研究での成果は、今後、長期的な投与による効果、副作用を検討する必要はあるが、これらの薬物をリード化合物としたHsp発現誘導化合物がSCA14の治療薬、さらには多くの神経変性症の治療薬となりうることが示された。同定された薬物は、アミロイド形成により発症するすべての神経変性疾患、アルツハイマー病、パーキンソン病、ハンチントン病、小脳脊髄変性症などの本質的な治療薬としても応用可能であると考えられる。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (13 results)

All 2020 2019 2018 2017

All Journal Article (13 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 13 results,  Open Access: 12 results,  Acknowledgement Compliant: 2 results)

  • [Journal Article] mTORC1 is involved in DGKβ-induced neurite outgrowth and spinogenesis.2020

    • Author(s)
      Nakai, H., Tsumagari, R., Maruo, K., Nakashima, A., Kikkawa, U., Ueda, S., Yamanoue, M., Saito, N., Takei, N., Shirai, Y.
    • Journal Title

      Neurochem. Int.

      Volume: 134

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Rac-Dependent Signaling from Keratinocytes Promotes Differentiation of Intradermal White Adipocytes2020

    • Author(s)
      Ueyama Takehiko、Sakuma Megumi、Nakatsuji Mio、Uebi Tatsuya、Hamada Takeshi、Aiba Atsu、Saito Naoaki
    • Journal Title

      Journal of Investigative Dermatology

      Volume: 140 Issue: 1 Pages: 75-84.e6

    • DOI

      10.1016/j.jid.2019.06.140

    • NAID

      120006733143

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Spinocerebellar ataxia type 14 caused by a nonsense mutation in the PRKCG gene2019

    • Author(s)
      Shirafuji T, Shimazaki H, Miyagi T, Ueyama T, Adachi N, Tanaka T, Hide I, Saito S, Sakai S
    • Journal Title

      Mol. Cell. Neurosci.

      Volume: 98 Pages: 46-53

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Differential S-palmitoylation of the human and rodent β3-adrenergic receptors.2019

    • Author(s)
      Adachi N, Hess DT, Kaku M, Ueda C, Numa C, Saito N.
    • Journal Title

      J Biol Chem.

      Volume: 15;294(7) Issue: 7 Pages: 2569-2578

    • DOI

      10.1074/jbc.ra118.004978

    • NAID

      120006604674

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Pharmacological induction of heat shock proteins ameliorates toxicity of mutant PKCγ in spinocerebellar ataxia type 142018

    • Author(s)
      Nakazono, A., Adachi, N., Takahashi, H., Seki, T., Hamada, D., Ueyama, T., Sakai, N. and Saito, N.
    • Journal Title

      J. Biol. Chem.

      Volume: 293 Issue: 38 Pages: 14758-14774

    • DOI

      10.1074/jbc.ra118.002913

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hearing vulnerability after noise exposure in a mouse model of reactive oxygen species overproduction2018

    • Author(s)
      Morioka Shigefumi、Sakaguchi Hirofumi、Yamaguchi Taro、Ninoyu Yuzuru、Mohri Hiroaki、Nakamura Takashi、Hisa Yasuo、Ogita Kiyokazu、Saito Naoaki、Ueyama Takehiko
    • Journal Title

      Journal of Neurochemistry

      Volume: 146 Issue: 4 Pages: 459-473

    • DOI

      10.1111/jnc.14451

    • NAID

      120006545101

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Roles of Cdc42 and Rac in Bergmann glia during cerebellar corticogenesis. Exp. Neurol.2018

    • Author(s)
      Sakamoto I, Ueyama T, Hayashibe M, Nakamura T, Mohri H, Kiyonari H, Shigyo M, Tohda C, Saito N.
    • Journal Title

      Exp. Neurol.

      Volume: 302 Pages: 57-67

    • DOI

      10.1016/j.expneurol.2017.12.003

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Role of Cysteine String Protein Alpha (CSPα) Phosphorylation at Serine 10, and 34, by Protein Kinase Cγ for Presynaptic Maintenance.2018

    • Author(s)
      Shirafuji T, Ueyama T, Adachi N, Yoshino KI, Sotomaru Y, Uwada J, Kaneoka A, Ueda T, Tanaka S, Hide I, Saito N, Sakai N
    • Journal Title

      J. Neurosci.

      Volume: 38 Issue: 2 Pages: 278-290

    • DOI

      10.1523/jneurosci.1649-17.2017

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Validation of Anti-CSPα, SNAP25, Tyrosine Hydroxylase, Ubiquitin, Cleaved Caspase 3, and pSer PKC Motif Antibodies for Utilization in Western Blotting2017

    • Author(s)
      Shirafuji T, Ueyama T, Tanaka S, Hide I, Saito N and Sakai N
    • Journal Title

      ACTA HISTOCHEMICA ET CYTOCHEMICA

      Volume: 50 Issue: 6 Pages: 177-180

    • DOI

      10.1267/ahc.17028

    • NAID

      130006285168

    • ISSN
      0044-5991, 1347-5800
    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Loss of the Phenolic Hydroxyl Group and Aromaticity from the Side Chain of Anti-Proliferative 10-Methyl-aplog-1, a Simplified Analog of Aplysiatoxin, Enhances Its Tumor-Promoting and Proinflammatory Activities2017

    • Author(s)
      Yusuke Hanaki, Masayuki Kikumori, Harukini Tokuda, Mutsumi Okamura, Shingo Dan, Naoko Adachi, Naoaki Saito, Ryo C. Yanagita, Kazuhiro Irie
    • Journal Title

      Molecules

      Volume: 22 Issue: 4 Pages: 631-631

    • DOI

      10.3390/molecules22040631

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Novel role of Rac-Mid1 signaling in medial cerebellar development.2017

    • Author(s)
      Nakamura T, Ueyama T, Ninoyu Y, Sakaguchi H, Choijookhuu N, Hishikawa Y, Kiyonari H, Kohta M, Sakahara M, de Curtis I, Kohmura E, Hisa Y, Aiba A, Saito N.
    • Journal Title

      Development

      Volume: 144 Issue: 10 Pages: 1863-1875

    • DOI

      10.1242/dev.147900

    • NAID

      120006363303

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Golgi-Associated Protein Kinase C-ε Is Delivered to Phagocytic Cups: Role of Phosphatidylinositol 4-Phosphate2017

    • Author(s)
      Hanes Cheryl M.、D’Amico Anna E.、Ueyama Takehiko、Wong Alexander C.、Zhang Xuexin、Hynes W. Frederick、Barroso Margarida M.、Cady Nathaniel C.、Trebak Mohamed、Saito Naoaki、Lennartz Michelle R.
    • Journal Title

      J. Immunol

      Volume: 199 Issue: 1 Pages: 271-277

    • DOI

      10.4049/jimmunol.1700243

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A novel Rac1-GSPT1 signaling pathway controls astrogliosis following central nervous system injury2017

    • Author(s)
      Ishii T, Ueyama T, Shigyo M, Kohta M, Kondoh T, Kuboyama T, Uebi T, Hamada T, Gutmann DH, Aiba A, Kohmura E, Tohda C, Saito N
    • Journal Title

      J Biol Chem

      Volume: 292 Issue: 4 Pages: 1240-1250

    • DOI

      10.1074/jbc.m116.748871

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant

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Published: 2017-04-28   Modified: 2021-02-19  

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