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

• Project/Area Number: 17H04032
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Kobe 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: ¥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。

Research Products

• [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
  • Peer Reviewed / Open Access
• [Journal Article] Rac-Dependent Signaling from Keratinocytes Promotes Differentiation of Intradermal White Adipocytes (2020)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Spinocerebellar ataxia type 14 caused by a nonsense mutation in the PRKCG gene (2019)
  • 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
  • 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
  • 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 14 (2018)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Hearing vulnerability after noise exposure in a mouse model of reactive oxygen species overproduction (2018)
  • 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
  • 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
  • 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
  • Peer Reviewed
• [Journal Article] Validation of Anti-CSPα, SNAP25, Tyrosine Hydroxylase, Ubiquitin, Cleaved Caspase 3, and pSer PKC Motif Antibodies for Utilization in Western Blotting (2017)
  • 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
  • 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 Activities (2017)
  • 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
  • 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
  • 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-Phosphate (2017)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel Rac1-GSPT1 signaling pathway controls astrogliosis following central nervous system injury (2017)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant