Analysis of TFG gene and development of treatment for motor neuron diseases

• Project/Area Number: 26461294
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: The University of Tokushima
• Principal Investigator: KAWARAI Toshitaka 徳島大学, 大学院医歯薬学研究部(医学系), 講師 (50614137)
• Co-Investigator(Kenkyū-buntansha): 梶 龍兒 徳島大学, 大学院医歯薬学研究部(医学系), 教授 (00214304)
• Co-Investigator(Renkei-kenkyūsha): IMOTOI Issei 徳島大学, 大学院医歯薬学研究部, 教授 (30258610) ; TAJIMA Atsushi 金沢大学, 医学系, 教授 (10396864)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 運動ニューロン病 / TFG / 運動ニューロン死 / 細胞内輸送 / 凝集体形成 / 小胞体 / ゴルジ体 / 筋萎縮性側索硬化症 / 痙性対麻痺 / 末梢神経障害

Outline of Final Research Achievements

We performed biological characterization of neural cells derived from hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) patient induced pluripotent stem cells (iPSCs), and revealed proteasome dysfunction when the iPSCs carrying the clinical mutation, Pro285Leu, in tropomyosin-receptor kinase fused gene (TFG). We also analyzed the animal model for HMSN-P, transgenic mice over expressing human mutant TFG, and demonstrated replication of intraneuronal aggregations, including TFG, optineurin, and TAR DNA binding protein 43 (TDP-43). The model mice are undergoing therapeutic trial using phenylbutyrate, which has been demonstrated to be clinically and pathologically effective to decrease Tau aggregation in transgenic mice via activation of autophagy.

Research Products

• [Journal Article] Proteasome impairment in neural cells derived from HMSN-P patient iPSCs. (2017)
  • Author(s): Murakami N, Imamura K, Izumi Y, Egawa N, Tsukita K, Enami T, Yamamoto T, Kawarai T, Kaji R, Inoue H.
  • Journal Title: Mol Brain Volume: 10 Issue: 1 Pages: 1-7
  • DOI: 10.1186/s13041-017-0286-y
  • NAID: 120005971847
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Exome sequencing identifies a novel intronic mutation in ENG that cause recurrence of pulmonary arteriovenous malformations. (2015)
  • Author(s): Kawarai T, Saji N, Miyamoto R, Sato T, Morino H, Orlacchio A, Oki R, Kimura K and Kaji R.
  • Journal Title: Journal of the Neurological Sciences Volume: 351 Issue: 1-2 Pages: 231-233
  • DOI: 10.1016/j.jns.2015.02.007
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Hereditary spastic paraplegia: a novel mutation and expansion of the phenotype variability in SPG10. (2014)
  • Author(s): Laura Carosi,Temistocle Lo Giudice, Martina Di Lullo, Federica Lombardi, Carla Babalini, Fabrizio Gaudiello, Girolama Alessandra Marfia, Roberto Massa, Toshitaka Kawarai, Antonio Orlacchio.
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: 85 Issue: 6 Pages: 989-921
  • DOI: 10.1136/jnnp-2014-308625
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Efficacy of deep brain stimulation in an adolescent patient with DYT11 myoclonus-dystonia (2014)
  • Author(s): 2.Kimura Y, Mihara M, Kawarai T, Kishima H, Sakai N, Takahashi M and Mochizuki H
  • Journal Title: Neurology and Clinical Neuroscience Volume: 2 Issue: 2 Pages: 57-59
  • DOI: 10.1111/ncn3.75
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] DYT6 in Japan-genetic screening and clinical characteristics of the patients. (2014)
  • Author(s): Miyamoto R, Koizumi H, Morino H, Kawarai T, Maruyama H, Mukai Y, Miyashiro A, Sako W, Izumi Y, Kawakami H, Kaji R.
  • Journal Title: Mov Disord. Volume: 29 Issue: 2 Pages: 278-280
  • DOI: 10.1002/mds.25745
  • Peer Reviewed
• [Journal Article] Hereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanisms. (2014)
  • Author(s): Temistocle Lo Giudice, Federica Lombardi, Filippo Maria Santorelli, Toshitaka Kawarai and Antonio Orlacchio.
  • Journal Title: Exp Neurol. Volume: 261 Pages: 518-539
  • DOI: 10.1016/j.expneurol.2014.06.011
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Animal model of HMSN-P (2016)
  • Author(s): Ryosuke Oki, Akie Tanabe, Toshitaka Kawarai, Nobuyuki Oka, Yuishin Izumi and Ryuji Kaji
  • Organizer: The 57th Annual Meeting of the Japanese Society of Neurology
  • Place of Presentation: 神戸コンベンションセンター（兵庫県・神戸市）
  • Year and Date: 2016-05-18
• [Presentation] Clinicopathological features of HMSN-P in the Kansai area of Japan. (2016)
  • Author(s): Toshitaka Kawarai, Koji Fujita, Yuishin Izumi, Mari Yoshida and Ryuji Kaji. Clinicopathological features of HMSN-P in the Kansai area of Japan
  • Organizer: The 57th Annual Meeting of the Japanese Society of Neurology
  • Place of Presentation: 神戸コンベンションセンター（兵庫県・神戸市）
  • Year and Date: 2016-05-18
• [Presentation] TFG変異による運動ニューロン疾患 (2015)
  • Author(s): 瓦井俊孝
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 新潟朱鷺メッセ(新潟県新潟市)
  • Year and Date: 2015-05-19
  • Invited
• [Presentation] 精神運動発育遅滞を伴う家族性小脳失調症で見つかったVWA3B遺伝子変異 (2014)
  • Author(s): 瓦井俊孝、田嶋敦、黒田由紀子、佐治直樹、寺澤英夫、清水洋孝、喜多也寸志、Antonio Orlacchio、宮本亮介、和泉唯信、三ツ井貴夫、井本逸勢、梶龍兒
  • Organizer: 日本人類遺伝学会第59回大会
  • Place of Presentation: タワーホテル船堀 (東京都江戸川区）
  • Year and Date: 2014-11-19 – 2014-11-22
• [Presentation] VWA3B mutated in a family with cerebellar ataxia with psychomotor retardation (2014)
  • Author(s): Toshitaka Kawarai, Atsushi Tajima, Yukiko Kuroda, Naoki Saji, Hideo Terasawa, Hirotaka Shimizu, Yasushi Kita, Antonio Orlacchio, Ryosuke Miyamoto, Yuishin Izumi, Takao Mitsui, Issei Imoto and Ryuji Kaji.
  • Organizer: 55th Annual Meeting of the Japanese Society of Neurology
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2014-05-21 – 2014-05-24
• [Book] 神経内科 (2015)
  • Author(s): 瓦井俊孝
  • Total Pages: 456
  • Publisher: 科学評論社
• [Book] 新規運動ニューロン病遺伝子TFGの機能解析 (2015)
  • Author(s): 瓦井俊孝
  • Total Pages: 256
  • Publisher: ブレインサイエンス振興財団
• [Book] 神経内科 (2015)
  • Author(s): 瓦井俊孝, 森垣龍馬, 沖 良祐, 和泉唯信, 後藤 惠, 梶 龍兒
  • Total Pages: 456
  • Publisher: 科学評論社
• [Book] ブレインサイエンス・レビュー2015 (2015)
  • Author(s): 瓦井俊孝
  • Total Pages: 252
  • Publisher: ブレインサイエンス振興財団