Toward developing novel therapeutic drugs that suppress oligomerization ofdisease-causing proteins in poluglutamine diseases

2012 Fiscal Year Final Research Report

• Project/Area Number: 23790982
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Niigata University
• Principal Investigator: TADA Masayoshi 新潟大学, 脳研究所, 助教 (10467079)
• Project Period (FY): 2011 – 2012
• Keywords: 脊髄小脳変性症 / ポリグルタミン病 / 重合体 / 治療

Research Abstract

Oligomerization of misfolded disease proteins plays a critical role in thepathogenesis of polyglutamine diseases. Increasing evidence suggests that soluble, nonfibrillaroligomers formed early in the pathogenic cascade are more toxic species than insoluble, mature amyloidfibrils or inclusions. To seek novel therapeutic drugs for polyglutamine diseases, we have already donea primary, high-throughput screen using a luciferase-based protein-fragment complementationanalysis (PCA) that can detect polyglutamine protein oligomers in living cells. In this study, weevaluated efficacies of compounds that showed more than 50% suppression of oligomerization in theprimary screen, using the following methods: [1] a fluorescence-based PCA system to directly visualizepolyglutamine protein oligomerization in living cells, and [2] a Caenorhabditis elegans model ofpolyglutamine disease. We found several promising compounds that suppress oligomer formation ofpolyglutamine proteins. We also tried to establish iPS cell lines from skin firoblasts of patients withMachado-Joseph disease [3].

Research Products

• [Journal Article] Coexistence of Huntington's disease and amyotrophic lateral sclerosis: a clinicopathologic study (2012)
  • Author(s): Tada M, Coon EA, Osmand AP, Kirby PA, Martin W, Wieler M, Shiga A, Shirasaki H, Tada M, Makifuchi T, Yamada M, Kakita A, Nishizawa M, Takahashi H, Paulson HL
  • Journal Title: Acta Neuropathol. Volume: 124 Pages: 749-760
• [Journal Article] Genotype-phenotype correlations in early onsetataxia with ocular motor apraxia andhypoalbuminaemia (2011)
  • Author(s): Yokoseki A, Ishihara T, Koyama A, Shiga A,Yamada M, Suzuki C, Sekijima Y, Maruta K,Tsuchiya M, Date H, Sato T, Tada M, Ikeuchi T,Tsuji S, Nishizawa M, Onodera O
  • Journal Title: Brain Volume: 134 Pages: 1387-1399
• [Presentation] ロシア・ヤクート人との比較によるSCA1発症に関わる環境・遺伝学的要因の検討 (2012)
  • Author(s): 他田正義,徳永純,Maksimova N, Varlamova M,堅田慎一,高橋俊昭, Nikolaeva I, Sukhomyasova A,土屋美由紀,池内健,小寺理,西澤正豊
  • Organizer: 日本神経学会学術大会
  • Year and Date: 20120500
• [Presentation] ポリグルタミン重合体形成阻害剤のスクリーニングを目的としたモデル線虫の構築 (2012)
  • Author(s): 徳永純,他田正義,高橋俊昭,高橋有香,鹿野智美,小山哲秀,堅田慎一,山中邦俊,小野寺理,西澤正豊
  • Organizer: 日本神経学会学術大会
  • Year and Date: 20120500
• [Presentation] ヒト疾患脳におけるポリグルタミン病重合体の検出 (2011)
  • Author(s): 高橋俊昭,石平悠,堅田慎一,他田正義,他田真理,佐藤俊哉,柿田明美,高橋均,小野寺理,西澤正豊
  • Organizer: 日本神経学会学術大会
  • Year and Date: 20110500
• [Presentation] 重合体形成阻害を標的としたポリグルタミン病の新規治療法開発 (2011)
  • Author(s): 他田正義,高橋俊昭,小野寺理,西澤正豊,Paulson Henry L
  • Organizer: 日本神経学会学術大会
  • Year and Date: 20110500
• [Book] 劣性遺伝性小脳失調症.小脳と運動失調:小脳はなにをしているのか (2013)
  • Author(s): 他田正義,小野寺理
  • Total Pages: 200-214
  • Publisher: 中山書店
• [Book] IP3 Receptors in Neurodegenerative Disorders: Spinocerebellar Ataxias and Huntington's and Alzheimer's Diseases. In Pathologies of Calcium Channels
  • Author(s): Tada M, Nishizawa M, and Onodera M
  • Publisher: Springer(in press)
• [Remarks]
  • URL: http://www.bri.niigata-u.ac.jp/neuroweb/laboratory/research_001.html