Elucidation of dysregulation of exocytosis in sporadic amyotrophic lateral sclerosis

• Project/Area Number: 16K15480
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: KATSUNO Masahisa 名古屋大学, 医学系研究科, 教授 (50402566)
• Co-Investigator(Kenkyū-buntansha): 石垣 診祐 名古屋大学, 医学系研究科, 寄附講座助教 (40378170)
• Project Period (FY): 2016-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2016: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 筋萎縮性側索硬化症 / 運動ニューロン / エクソサイトーシス / 糖尿病 / インスリン / 運動ニューロン疾患 / TDP-43

Outline of Final Research Achievements

TAR DNA-binding protein 43 kDa (TDP-43) encoded by TARDBP gene is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder affecting both upper and lower motor neurons. Besides motor symptoms, ALS patients often develop non-neuronal signs including glucose intolerance, but underlying pathomechanism is still controversial: impaired insulin secretion and/or insulin resistance. Here we show that ALS subjects have reduced early phase insulin secretion and that nuclear localization TDP-43 is lost in the islets of autopsied pancreas of ALS. Loss of TDP-43 inhibits early phase insulin secretion in both Min6 cells and pancreatic beta cell-specific Tardbp knock-out mice. Nuclear loss of TDP-43 is thus implicated in not only selective loss of motor neurons, but glucose intolerance due to impaired insulin secretion at an early stage of ALS.

Research Products

• [Journal Article] Altered tau isoform ratio caused by loss of Fus and Sfpq function leads to FTLD-like phenotypes (2017)
  • Author(s): Ishigaki S, Fujioka Y, Okada Y, Riku Y, Udagawa T, Honda D, Yokoi S, Endo K, Ikenaka K, Takagi S, Iguchi Y, Sahara N, Takashima A, Okano H, Yoshida M, Warita H, Aoki M, Watanabe H, Okado H, Katsuno H, Sobue G.
  • Journal Title: Cell Reports Volume: 18 Issue: 5 Pages: 1118-1131
  • DOI: 10.1016/j.celrep.2017.01.013
  • Peer Reviewed / Open Access
• [Journal Article] Decreased Peak Expiratory Flow Associated with Muscle Fiber-Type Switching in Spinal and Bulbar Muscular Atrophy. (2016)
  • Author(s): Yamada S, Hashizume A, Hijikata Y, Inagaki T, Suzuki K, Kondo N, Kawai K, Noda S, Nakanishi H, Banno H, Hirakawa A, Koike H, Halievski K, Jordan CL, Katsuno M, Sobue G.
  • Journal Title: PLoS One. Volume: 11(12) Issue: 12 Pages: e0168846-e0168846
  • DOI: 10.1371/journal.pone.0168846
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Exosome secretion is a key pathway for clearance of pathological TDP-43. (2016)
  • Author(s): Iguchi Y,, Eid L,, Parent M,, Soucy G,, Bareil C,, Riku Y,, Kawai K,, Takagi S,, Yoshida M,, Katsuno M,, Sobue G., Julien JP.
  • Journal Title: Brain Volume: 139 Issue: 12 Pages: 3187-3201
  • DOI: 10.1093/brain/aww237
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 神経変性疾患モデルにおけるタクロリムスとその誘導体の治療効果 (2016)
  • Author(s): 藤内玄規, 勝野雅央, 足立弘明, 佐橋健太郎, 近藤直英, 中辻秀朗, 飯田円, 祖父江元
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県 横浜市)
  • Year and Date: 2016-11-30
• [Presentation] Loss of SFPQ, an intra-nuclear counterpart of FUS cause FTLD-like phenotypes. (2016)
  • Author(s): Fujioka Y, Ishigaki S, Yokoi S, Honda D, Okado H, Watanabe H, Katsuno M, Sobue G.
  • Organizer: Neuroscience 2016
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Accumulation of phosphorylated tau in neurons in FUS-silenced mice. (2016)
  • Author(s): Ishigaki S, Fujioka Y, Honda D, Yokoi S, Endo K, Okado H, Watanabe H, Katsuno M, Takashima A, Sobue G.
  • Organizer: Neuroscience 2016
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] 神経変性疾患の発症前病態と先制治療の開発 (2016)
  • Author(s): 勝野雅央
  • Organizer: 日本内科学会東海支部主催第66回生涯教育講演会
  • Place of Presentation: 名古屋国際会議場(愛知県 名古屋市)
  • Invited