Expression and role of autophagy-related molecules in motor neuron disease

• Project/Area Number: 17K16118
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: Tohnai Genki 名古屋大学, 医学系研究科, 特任助教 (00748353)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 運動ニューロン疾患 / SBMA / ALS / 球脊髄性筋萎縮症 / 筋萎縮性側索硬化症 / TBK1 / 神経変性疾患 / 運動ニューロン

Outline of Final Research Achievements

In this study, we analyzed frequencies and characteristics of TBK1 gene variants in Japanese patients with amyotrophic lateral sclerosis (ALS). TBK1 variants were frequently detected in ALS patients, suggesting that variations in TBK1 could be related to ALS. We found that the loss of function (LoF) variants rendered TBK1 unable to bind to optineurin in immunoprecipitation. Decreased expression of TBK1 was observed in the lymphocytes of patients with TBK1 LoF variants. Furthermore, decreased expression of TBK1 was observed in the spinal and bulbar muscular atrophy (SBMA) model cells, the expression of TBK1 was increased on administration of SBMA therapeutic agent.
Our findings suggest that TBK1 is involved in the pathogenesis of motor neuron diseases and further indicate that it may be a potential therapeutic target.

Academic Significance and Societal Importance of the Research Achievements

本研究は、運動ニューロン疾患のタンパク質品質管理機構におけるTBK1の役割の解析とTBK1と病因分子との相互作用解明を目的としている。TBK1が運動ニューロン疾患であるALSとSBMAにおいて病態に関与する可能性が示唆されたことで、運動ニューロン疾患共通の機能異常・細胞死のメカニズムの解明が期待できる。またTBK1シグナリングを標的とした治療法を模索することで運動ニューロン疾患全般に応用可能な治療法が開発できる可能性がある。

Research Products

• [Journal Article] Multi-Ethnic Comparison of the Characteristics of Amyotrophic Lateral Sclerosis-Related TBK1 Gene Variants (2019)
  • Author(s): Tohnai Genki、Nakamura Ryoichi、Nakatochi Masahiro、Atsuta Naoki、Katsuno Masahisa、Sobue Gen
  • Journal Title: Journal of Neurology & Neuromedicine Volume: 4 Issue: 1 Pages: 7-11
  • DOI: 10.29245/2572.942x/2019/1.1236
  • Peer Reviewed / Open Access
• [Journal Article] Frequency and characteristics of the TBK1 gene variants in Japanese patients with sporadic amyotrophic lateral sclerosis (2018)
  • Author(s): Tohnai Genki、Nakamura Ryoichi、Sone Jun、Nakatochi Masahiro、Yokoi Daichi、Katsuno Masahisa、Watanabe Hazuki、Watanabe Hirohisa、Ito Mizuki、Li Yuanzhe、Izumi Yuishin、et al. Atsuta Naoki、Sobue Gen
  • Journal Title: Neurobiology of Aging Volume: 64 Pages: 158.e15-158.e19
  • DOI: 10.1016/j.neurobiolaging.2017.12.005
  • Peer Reviewed
• [Presentation] Frequency and characteristics of the TBK1 gene variants in Japanese patients with sporadic ALS (2018)
  • Author(s): 藤内 玄規, 中村 亮一, 曽根 淳, 中杤 昌弘, 横井 大知, 勝野 雅央, 和泉 唯信, 森田 光哉, 谷口 彰, 桑原 聡, 阿部 康二, 溝口 功一, 青木 正志, 服部 信孝, 辻 省次, 梶 龍兒, 熱田 直樹, 祖父江 元
  • Organizer: 第59回日本神経学会学術大会