Integrative understanding and therapeutic application of seamless degenerative processes based on Hippo pathway

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H02655
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Okazawa Hitoshi 東京医科歯科大学, 難治疾患研究所, 教授 (50261996)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: TRIAD / Hippo pathway / ネクローシス / 神経変性 / 細胞死 / YAP / hnRNP

Outline of Final Research Achievements

In this project, we intended to define the new "Hippo pathway dependent necrosis", which the PI discovered as transcriptional repression-induced atypical neuronal death (TRIAD) in 2007 (Hoshino et al, JCB 2007), as a pathological concept that can conclusively explain the seamless progression of neurodegenerative pathologies. In parallel, we intended to develop a new therapeutics strategy targeting on this new necrosis. Consequently, we have identified new molecules regulating TRIAD/Hippo-dependent necrosis, have proven the existence of TRIAD/Hippo-dependent necrosis in human and mouse neurodegenerative states, and revealed that the suppression of TRIAD/Hippo-dependent necrosis by using AAV-vector or chemicals successfully inhibited the progression of symptoms and pathologies in mouse models of multiple neurodegenerative diseases.

Free Research Field

神経内科学、神経科学、神経病理学

Academic Significance and Societal Importance of the Research Achievements

神経変性疾患（ハンチントン病、アルツハイマー病など）には、現時点で根本治療薬（病態修飾薬）が存在しない。本研究成果は、新しいネクローシスサブタイプ（Hippo経路依存的細胞死もしくはTRIAD）の存在を示し、その分子経路を明らかにした点で、学術的に高い価値を有するのみならず、新規細胞死を標的とする新たな治療戦略が治療困難な神経変性疾患に対して有効であることを示した点で、社会的にも極めて有意義であったと考える。