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

2019 Fiscal Year Final Research Report

• 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
• Keywords: 進行性核上性麻痺 / タウオパチー / タウ

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.

Free Research Field

神経内科学、神経遺伝学、神経病理学

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。