Explore a novel mechanism for neurodegenerative disease using Caspr deficient mutant mice

• Project/Area Number: 23591241
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: TAKAGISHI Yoshiko 名古屋大学, 環境医学研究所, 助教 (50024659)
• Research Collaborator: KATANOSAKA Kimiaki 中部大学, 生命健康科学部・生命医科学科, 准教授 ; MIZOGUCHI Hiroyuki 名古屋大学, 環境医学研究所・次世代創薬研究センター, 助教
• Project Period (FY): 2011-04-28 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 神経変性疾患 / ランビエ絞輪 / パラノード / 遺伝性疾患マウス / 神経筋伝達 / 神経変性 / 興奮伝導 / 骨格筋 / 有髄神経線維 / 神経軸索変性 / 神経細胞死 / ランビエの絞輪 / 軸索変性 / ミュータントマウス / 軸索骨格 / ニューロフィラメント

Outline of Final Research Achievements

We identified a mutation of the Caspr gene in a mouse mutant shambling (shm). We analyzed dysfunction of the paranode at nodes of Ranvier and impaired nerve conduction in myelinated nerves of shm mice. The shm mice manifest the progressive neurological defect as mice age. We studied a pathophysiological process of the disease in the nervous system of shm mice and found that axons and neurons were severely damaged and resultant loss of neurons occurred in various regions of the nervous system in aged mice but not in young or adult mice. This study is a first demonstration of neuron death in the nervous system among the paranodal mutants. Further in this study we identified various parallelisms between shm mice and human neurodegenerative disease. We would like to propose that our study provides a novel prospect in a study to explore a mechanism of human neurodegenerative disease.

Research Products

• [Presentation] Impaired axon-glia interactions cause axonal degeneration and cell death of neurons in the cerebellum of Caspr-deficient shambling mice with progressive neurological phenotypes in aging. (2014)
  • Author(s): Yoshiko Takagishi, Hiroki Oohori, Hiroyuki Mizoguchi
  • Organizer: Society for Neuroscience, Neuroscience2014
  • Place of Presentation: Washington Convention Center (Washington DC, USA)
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] ランビエ絞輪パラノードに異常を持つshamblingマウスの小脳では、加齢によってプルキンエ細胞の軸索変性と細胞死が進行する (2014)
  • Author(s): 大堀洋揮 (Hiroki Oohori), 髙岸芳子 (Yoshiko Takagishi)
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: パシフィコ横浜 (横浜)
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Axonal pathology in myelinated nerves of a Caspr mutant mouse with deficient paranodal junctions at the paranode. (2013)
  • Author(s): Yoshiko Takagishi, Kimiaki Katanosaka, Ikuma Sasaki, Yoshiharu Murata
  • Organizer: 43th Annual Meeting of Society for Neuroscience
  • Place of Presentation: San Diego, USA
• [Presentation] 有髄神経線維パラノードタンパクに遺伝子変異を持つshamblingマウスにみられる神経軸索変性の分子基盤 (2013)
  • Author(s): 高岸芳子, 佐々木郁磨, 村田善晴
  • Organizer: Neuro2013（第36回日本神経科学大会・第56回日本神経化学会大会・第23回日本神経回路学会大会）
  • Place of Presentation: 国立京都国際会館、京都
• [Presentation] Defect of neuron-glia interaction at the paranode alters the axonal structure and causes autophagic neuronal cell death in shambling mice with a Caspr mutation (2012)
  • Author(s): Yoshiko Takagishi, Yusuke Yanagi, Ichie Koda, Yoshiharu Murata.
  • Organizer: Society for Neuroscience, Neuroscience 2012
  • Place of Presentation: New Orleans LA, USA
• [Presentation] 有髄神経線維パラノーダルジャンクションの欠失がもたらしたオートファジー様神経細胞死 (Disruption of the paranodal junction in myelinated nerves causes the autophagic cell death of neurons in aged shambling mice with a Caspr mutation: Electron microscopic study) (2012)
  • Author(s): 高岸芳子(Yoshiko Takagishi), 鴻田一絵（Ichie Koda）, 村田善晴(Yoshiharu Murata)
  • Organizer: The 35th Annual Meeting of the Japan Neuroscience Society (第35回日本神経科学大会)
  • Place of Presentation: Nagoya Congress Centre (愛知県名古屋市名古屋国際会議場)