In vivo analyses of networks in ALS-causing genes using fly models

• Project/Area Number: 24591286
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: FUJIKAKE Nobuhiro 独立行政法人国立精神・神経医療研究センター, 神経研究所疾病研究第四部, 科研費研究員 (60467595)
• Project Period (FY): 2012-04-01 – 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 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 神経分子病態学 / 遺伝学 / 神経科学 / 筋萎縮性側索硬化症 / TDP-43 / dynactin 1 / 神経変性疾患 / ショウジョウバエ / 遺伝子 / ＴＤＰ－４３

Outline of Final Research Achievements

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease which is characterized by selective motor neuron degeneration in brain and spinal cord. Recently, many genes which function in various cellular events have been identified as ALS-causing genes. To elucidate the common pathomechanisms and therapeutic targets of ALS caused by various genes, we analyzed networks in ALS-causing genes using ALS model flies. In this study, we successfully show that toxicity of TDP-43, an ALS-causing gene, is evoked by dysfunction of microtubule-dependent transport, and revealed that activation of microtubule-dependent transport is a new therapeutic target for AlS.

Research Products

• [Journal Article] p62 plays a protective role in the autophagic degradation of polyglutamine protein oligomers in polyglutamine disease model flies. (2015)
  • Author(s): Saitoh Y, Fujikake N, Okamoto Y, Popiel HA, Hatanaka Y, Ueyama M, Suzuki M, Gaumer S, Murata M, Wada K, Nagai Y.
  • Journal Title: J Biol Chem Volume: 290 Issue: 3 Pages: 1442-53
  • DOI: 10.1074/jbc.m114.590281
  • Peer Reviewed / Open Access
• [Journal Article] その他の FTLD―異常蛋白の視点から (2015)
  • Author(s): 上山盛夫、藤掛伸宏、永井義隆
  • Journal Title: Clinical Neuroscience Volume: 33 Pages: 312-4
• [Journal Article] VPS35 dysfunction impairs lysosomal degradation of α-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson's disease. (2014)
  • Author(s): Miura E, Hasegawa T, Konno M, Suzuki M, Sugeno N, Fujikake N, Geisler S, Tabuchi M, Oshima R, Kikuchi A, Baba T, Wada K, Nagai Y, Takeda A, Aoki M.
  • Journal Title: Neurobio Dis Volume: 71 Pages: 1-13
  • DOI: 10.1016/j.nbd.2014.07.014
  • Peer Reviewed
• [Journal Article] Identification of ter94, Drosophila VCP, as a strong modulator of motor neuron degeneration induced by knockdown of Caz, Drosophila FUS (2014)
  • Author(s): Azuma Y., Tokuda T., Shimamura M., Kyotani A., Sasayama H., Yoshida T., Mizuta I., Mizuno T., Nakagawa M., Fujikake N., Ueyama M., Nagai Y., Yamaguchi M
  • Journal Title: Hum. Mol. Genet Volume: 23(13) Issue: 13 Pages: 3467-3480
  • DOI: 10.1093/hmg/ddu055
  • Peer Reviewed
• [Journal Article] コンフォメーション病としての神経変性疾患 (2013)
  • Author(s): 永井義隆、藤掛伸宏
  • Journal Title: ファルマシア Volume: 49 Pages: 849-853
  • NAID: 110009995811
• [Journal Article] Knockdown of the Drosophila Fused in Sarcoma (FUS) homologue causes deficient locomotive behavior and shortening of motoneuron terminal branches. (2012)
  • Author(s): Sasayama, H., Shimamura, M., Tokuda, T., Azuma, Y., Yoshida, T., Mizuno, T., Nakagawa, M., Fujikake, N., Nagai, Y. and Yamaguchi, M
  • Journal Title: PLoS ONE Volume: 7(6), Issue: 6 Pages: e39483-e39483
  • DOI: 10.1371/journal.pone.0039483
  • Peer Reviewed
• [Presentation] ショウジョウバエから始める神経変性疾患研究 ～TDP-43輸送の障害はオリゴマー化を促進し、 神経変性を惹き起こす～ (2014)
  • Author(s): 藤掛伸宏、畑中悠佑、長野清一、斉藤勇二、荒木敏之、和田圭司、永井義隆
  • Organizer: 教育研修棟竣工記念シンポジウム
  • Place of Presentation: 国立精神・神経医療研究センター教育研修棟、東京
  • Year and Date: 2014-06-30
  • Invited
• [Presentation] DCTN1依存的輸送の障害はTDP-43のオリゴマー形成を促進する (2014)
  • Author(s): 藤掛伸宏、木村展之、長野清一、斉藤勇二、横関明男、小野寺理、和田圭司、永井義隆
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡国際会議場、福岡
  • Year and Date: 2014-05-14
• [Presentation] Oligomerization of TDP-43 is triggered by impairment of microtubule-dependent transport, leading to neurodegeneration in Drosophila (2013)
  • Author(s): Fujikake N, Kimura N, Saitoh Y, Suzuki M, Yokoseki A, Onodera O, Wada K, Nagai Y
  • Organizer: BRAI 2013
  • Place of Presentation: Sheraton San Diego Hotel & Marina, San Diego, USA
• [Presentation] Impairment of microtubule-dependent transport of TDP-43 triggers its aggregation, leading to neurodegeneration in Drosophila models of TDP-43 proteinopathies (2013)
  • Author(s): Fujikake N, Kimura N, Saitoh Y, Suzuki M, Yokoseki A, Onodera O, Wada K, Nagai Y
  • Organizer: SfN2013
  • Place of Presentation: San Diego Convention Center, San Diego, USA
• [Presentation] 微小管依存的輸送系の障害はTDP-43のオリゴマー形成を促進し、FTLDにおける神経変性を惹き起こす (2013)
  • Author(s): 藤掛伸宏
  • Organizer: 認知症研究を知る若手研究者の集まり2013
  • Place of Presentation: 和光純薬湯河原研修所、静岡県
• [Presentation] DCTN1依存的輸送の障害によりTDP-43発現ショウジョウバエの神経変性は増悪する (2013)
  • Author(s): 藤掛伸宏、木村展之、長野清一、斉藤勇二、横関明男、小野寺理、和田圭司、永井義隆
  • Organizer: 第54回日本神経学会学術大会
  • Place of Presentation: 東京国際フォーラム、東京都
• [Presentation] Aggregation of TDP-43 is triggered by insufficiency of microtubule-dependent transport in the cytoplasm, leading to neurodegeneration in Drosophila (2013)
  • Author(s): Fujikake N., Kimura N., Saitoh Y., Yokoseki A., Onodera O., Wada K., Nagai Y.
  • Organizer: 11 th International Conference on Alzheimer's & Parkinson's Diseases (AD/PD 2013)
  • Place of Presentation: Florence, Italy
• [Presentation] 微小管依存的輸送の障害はTDP-43の細胞質蓄積、オリゴマー形成を促進し、ALSにおける神経変性を惹き起こす (2012)
  • Author(s): 藤掛 伸宏, 木村 展之, 斉藤 勇二, 横関 明男, 小野寺 理, 和田 圭司, 永井義隆
  • Organizer: 第35回日本神経科学大会
  • Place of Presentation: 名古屋国際会議場、愛知
• [Presentation] Disruption of microtubule-dependent transport of TDP-43 triggers aggregation of TDP-43, leading to neurodegeneration in Drosophila models of human disease (2012)
  • Author(s): Fujikake N., Saitoh Y., Yokoseki A., Onodera O., Wada K., Nagai Y.
  • Organizer: 第10回日本ショウジョウバエ研究会
  • Place of Presentation: 東京慈恵会医科大学、東京
• [Presentation] TDP-43とFUSはショウジョウバエモデルにおいて 相乗的に神経変性を惹き起こす (2012)
  • Author(s): 藤掛 伸宏, 高橋 光里, 斉藤 勇二, 横関 明男, 小野寺 理, 和田 圭司, 永井義隆
  • Organizer: 第53回日本神経学会学術大会
  • Place of Presentation: 東京国際フォーラム、東京
• [Presentation] Exosome-mediated cell-to-cell transmission of heat shock proteins contributes to the maintenance of protein homeostasis (2012)
  • Author(s): Takeuchi T., Fujikake N., Wada K., Nagai Y.
  • Organizer: EMBO Symposium on Quality Control
  • Place of Presentation: Heidelberg, Germany
• [Presentation] Aggravation of neurodegeneration by high-nutrient diet in Drosophila models of neurodegenerative diseases (2012)
  • Author(s): Suzuki M., Fujikake N., Wada K., Nagai Y.
  • Organizer: Keystone Symposia on Aging and Diseases of Aging
  • Place of Presentation: Sheraton Miyako Hotel Tokyo, Tokyo
• [Presentation] ポリグルタミン病モデルショウジョウバエの病態においてp62は保護的に機能している (2012)
  • Author(s): 斉藤勇二、藤掛伸宏、岡本佑馬、和田圭司、永井義隆
  • Organizer: 第53回日本神経学会学術大会
  • Place of Presentation: 東京国際フォーラム、東京
• [Presentation] SCA6トランスジェニックショウジョウバエによるCav2.1のCTF毒性の検証 (2012)
  • Author(s): 石黒太郎、石川欽也、藤掛伸宏、永井義隆、水澤英洋
  • Organizer: 第53回日本神経学会学術大会
  • Place of Presentation: 東京国際フォーラム、東京
• [Presentation] パーキンソン病モデルショウジョウバエにおけるα-synuclein毒性はglucocerebrosidaseの機能喪失により増悪する (2012)
  • Author(s): 鈴木マリ、藤掛伸宏、和田圭司、永井義隆
  • Organizer: 第35回日本神経科学会
  • Place of Presentation: 名古屋国際会議場、愛知