Pathomechanism study of progressive supranuclear palsy based on genetic analysis in familial progressive supranuclear palsy

• Project/Area Number: 16K09663
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Hokkaido University
• Principal Investigator: Yabe Ichiro 北海道大学, 医学研究院, 准教授 (60372273)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 進行性核上性麻痺 / タウオパチー / タウ / タウオパチィー / 脳・神経

Outline of Final Research Achievements

We performed a retrospective pathological and genetic study of a family with PSP-like phenotypes and a genetic study of probands in four pedigrees with PSP-like syndrome and 41 sporadic PSP-like syndrome cases. We identified a missense mutation of the bassoon (BSN) gene in a family with PSP-like syndrome. The neuropathological findings showed a novel three+four repeat tauopathy. In addition, three missense BSN mutations, which were rare in healthy subject databases, were found in four sporadic cases. Western blot analysis of tau following the overexpression of wild-type or mutated BSN revealed the possibility that wild-type BSN reduced tau accumulation, while mutated BSN lost this function. Our study demonstrated the clinical and pathological features of PSP-like syndrome due to BSN mutations. The neurodegenerative disorder associated with this proband’s pedigree is a novel tauopathy, differing from known dementia and parkinsonism syndromes, including PSP.

Academic Significance and Societal Importance of the Research Achievements

世界で初めてBSN遺伝子と神経変性の関係を見出した研究である。本研究を引用しBassoon proteinopathyという疾患概念も提唱されつつある(Schattling B, et al. Nat Neurosci 2019; 22: 887-896) 。加えて、多系統萎縮症や多発性硬化症などの他の神経変性疾患との関連も示唆されつつある。これらのことから神経変性病態解明に向けて新たな機序が見出される可能性があり、その意義は大きいと考える。

Research Products

• [Journal Article] Mutations in bassoon in individuals with familial and sporadic progressive supranuclear palsy-like syndrome (2018)
  • Author(s): Yabe I, Yaguchi H, Kato Y, Miki Y, Takahashi H, Tanikawa S, Shirai S, Takahashi I, Kimura M, Hama Y, Matsushima M, Fujioka S, Kano T, Watanabe M, Nakagawa S, Kunieda Y, Ikeda Y, Hasegawa M, Nishihara H, Ohtsuka T, Tanaka S, Tsuboi Y, Hatakeyama S, Wakabayashi K, Sasaki H
  • Journal Title: Scientific Reports Volume: 8 Pages: 819-819
  • DOI: 10.1038/s41598-018-19198-0
  • NAID: 120006377499
  • Peer Reviewed / Open Access
• [Presentation] Identification of a gene associated with PSP (2019)
  • Author(s): 矢部一郎
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] A part of tauopathy may be caused by mutations in bassoon. (2018)
  • Author(s): Yabe I, Yaguchi H, Kato Y, Miki Y, Takahashi H, Shirai S, Takahashi I, Kano T, Fujioka S, Watanabe M, Nakagawa S, Kunieda Y, Ikeda Y, Hasegawa M, Nishihara H, Tanaka S, Tsuboi Y, Hatakeyama S, Wakabayashi K, Sasaki H.
  • Organizer: 第59回日本神経学会学術大会
  • Int'l Joint Research
• [Presentation] Mutations in bassoon in individuals with familial and sporadic progressive supranuclear palsy-like syndrome (2017)
  • Author(s): Yabe I, Yaguchi H, Kato Y, Miki Y, Takahashi H, Tanikawa S, Shirai S, Takahashi I, Fujioka S, Watanabe M, Nakagawa S, Kunieda Y, Ikeda Y, Hasegawa M, Nishihara H, Tanaka S, Tsuboi Y, Hatakeyama S, Wakabayashi K, Sasaki H
  • Organizer: 23rd World Congress of Neurology
  • Int'l Joint Research
• [Presentation] 家族性進行性核上性麻痺症候群家系の遺伝子解析結果に基づいた孤発性進行性核上性麻痺の遺伝子解析研究 (2016)
  • Author(s): 矢部一郎 他
  • Organizer: 第57回日本神経学会学術集会
  • Place of Presentation: 神戸コンベンションセンター（兵庫県神戸市）