A drug screening system for ALS by automated, quantitative motility analysis of C. elegans ALS model

• Project/Area Number: 26670439
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: Sobue Gen 名古屋大学, 医学(系)研究科(研究院), 特任教授 (20148315)
• Co-Investigator(Kenkyū-buntansha): Katsuno Masahisa 名古屋大学, 大学院医学系研究科, 教授 (50402566)
• Co-Investigator(Renkei-kenkyūsha): Mori Ikue 名古屋大学, 大学院理学系研究科, 教授 (90219999)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 筋萎縮性側索硬化症 / 薬剤スクリーニング / 低分子化合物 / トランスレーショナルリサーチ / 線虫

Outline of Final Research Achievements

There has not been reliable method for in vivo high-throughput quantification of the drug effects. Recently our collaborator developed a real-time computer vision system, the Multi worm tracker(WMT), that can quantify the behavior of dozens of worms. Using this system, we explored the effective drug for the ALS model animals, dnc-1KD worm, in which the dynactin 1 is knocked down in the motor neurons. This model shows the motor neuronal degeneration, and it mimics a several significant features of ALS pathology. We first chose rapamycin as a positive control and showed the effect in a dose dependent manner. Next, we screened the 50 drugs and identified two compounds which significantly rescued the motor deficit of the worm. Interestingly, one of the drug was Riluzole, which is one of the only two drugs approved for ALS in Japan. The other drug X is an anti-hypertensive drug. This method allow us to complete a drug screen in a few weeks compared with a few years when using rodent models.

Research Products

• [Journal Article] A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression of TTN. (2016)
  • Author(s): Watanabe H, Atsuta N, Hirakawa A, Nakamura R, Nakatochi M, Ishigaki S, Iida A, Sobue G.
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: in press Issue: 8 Pages: 851-8
  • DOI: 10.1136/jnnp-2015-311541
  • Peer Reviewed
• [Journal Article] Next-generation sequencing of 28 ALS-related genes in a Japanese ALS cohort (2016)
  • Author(s): Ryoichi Nakamura, Jun Sone, Naoki Atsuta, Genki Tohnai, Hazuki Watanabe, Daichi Yokoi, Masahiro Nakatochi, Hirohisa Watanabe, Mizuki Ito, Jo Senda, Masahisa Katsuno, Fumiaki Tanaka, Yuanzhe Li, Yuishin Izumi, Mitsuya Morita, Akira Taniguchi, Osamu Kano, Masaya Oda, Satoshi Kuwabara, Koji Abe.
  • Journal Title: Neurobiology of Aging Volume: 39 Pages: 219-219
  • DOI: 10.1016/j.neurobiolaging.2015.11.030
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Head Lift Exercise Improves Swallowing Dysfunction in Spinal and Bulbar Muscular Atrophy (2015)
  • Author(s): Mano T, Katsuno M, Banno H, Suzuki K, Suga N, Hashizume A, Araki A, Hijikata Y, Tanaka S, Takatsu J, Watanabe H, Yamamoto M, Sobue G
  • Journal Title: Eur Neurol Volume: 74 Issue: 5-6 Pages: 251-258
  • DOI: 10.1159/000431088
  • Peer Reviewed
• [Journal Article] Overexpression of hepatocyte growth factor in SBMA model mice has an additive effect on combination therapy with castration. (2015)
  • Author(s): Ding Y, Adachi H, Katsuno M, Huang Z, Jiang YM, Kondo N, Iida M, Tohnai G, Nakatsuji H, Funakoshi H, Nakamura T, Sobue G
  • Journal Title: Biochem Biophys Res Commun Volume: 468 Issue: 4 Pages: 677-683
  • DOI: 10.1016/j.bbrc.2015.11.015
  • Peer Reviewed
• [Journal Article] Myotonia-like symptoms in a patient with spinal and bulbar muscular atrophy. (2015)
  • Author(s): Araki K, Nakanishi H, Nakamura T, Atsuta N, Yamada S, Hijikata Y, Hashizume A, Suzuki K, Katsuno M, Sobue G
  • Journal Title: Neuromuscul Disord. Volume: 25 Issue: 11 Pages: 913-915
  • DOI: 10.1016/j.nmd.2015.08.006
  • Peer Reviewed
• [Journal Article] Silencing neuronal mutant androgen receptor in a mouse model of spinal and bulbar muscular atrophy. (2015)
  • Author(s): Sahashi K, Katsuno M, Hung G, Adachi H, Kondo N, Nakatsuji H, Tohnai G, Iida M, Bennett CF, Sobue G.
  • Journal Title: Hum Mol Genet. Volume: 24(21) Issue: 21 Pages: 5985-94
  • DOI: 10.1093/hmg/ddv300
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] FUS regulates AMPA receptor function and FTLD/ALS-associated behaviour via GluA1 mRNA stabilization. (2015)
  • Author(s): Udagawa, T., Fujioka, Y., Tanaka, M., Honda, D., Yokoi, S., Riku, Y., Ibi, D., Nagai, T., Yamada, K., Watanabe, H., Katsuno, M., Inada, T., Ohno, K., Sokabe, M., Okado, H., Ishigaki S*., and Sobue, G.
  • Journal Title: Nat Commun Volume: 6 Issue: 1 Pages: 7098-7098
  • DOI: 10.1038/ncomms8098
  • Peer Reviewed / Open Access
• [Journal Article] A functional scale for spinal and bulbar muscular atrophy: Cross-sectional and longitudinal study. (2015)
  • Author(s): Hashizume A, Katsuno M, Suzuki K, Banno H, Suga N, Mano T, Araki A, Hijikata Y, Grunseich C, Kokkinis A, Hirakawa A, Watanabe H, Yamamoto M, Fischbeck KH, Sobue G
  • Journal Title: Neuromuscul Disord. Volume: 25 Issue: 7 Pages: 554-562
  • DOI: 10.1016/j.nmd.2015.03.008
  • Peer Reviewed
• [Journal Article] Astrocyte-Derived TGF-β1 Accelerates Disease Progression in ALS Mice by Interfering with the Neuroprotective Functions of Microglia and T Cells. (2015)
  • Author(s): Endo F, Komine O, Fujimori-Tonou N, Katsuno M, Jin S, Watanabe S, Sobue G, Dezawa M, Wyss-Coray T, Yamanaka K
  • Journal Title: Cell Reports Volume: 11 Issue: 4 Pages: 592-604
  • DOI: 10.1016/j.celrep.2015.03.053
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Pioglitazone suppresses neuronal and muscular degeneration caused by polyglutamine-expanded androgen receptors. (2015)
  • Author(s): Iida M, Katsuno M, Nakatsuji H, Adachi H, Kondo N, Miyazaki Y, Tohnai G, Ikenaka K, Watanabe H, Yamamoto M, Kishida K, Sobue G
  • Journal Title: Hum Mol Genet. Volume: 24 Issue: 2 Pages: 314-329
  • DOI: 10.1093/hmg/ddu445
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Factors affecting longitudinal functional decline and survival in amyotrophic lateral sclerosis patients. (2014)
  • Author(s): Watanabe H, Atsuta N, Nakamura R, Hirakawa A, Watanabe H, Ito M, Senda J, Katsuno M, Izumi Y, Morita M, Tomiyama H, Taniguchi A, Aiba I, Abe K, Mizoguchi K, Oda M, Kano O, Okamoto K, Kuwabara S, Hasegawa K, Imai T, Aoki M, Tsuji S, Nakano I, Kaji R, Sobue G.
  • Journal Title: Amyotroph Lateral Scler Frontotemporal Degener. Volume: Epub ahead of print Issue: 3-4 Pages: 230-6
  • DOI: 10.3109/21678421.2014.990036
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Perspectives on therapeutic research for ALS -General review of therapeutics, and edaravone treatment- (2016)
  • Author(s): 祖父江 元
  • Organizer: 大韓神経筋肉疾患学会
  • Place of Presentation: Seoul(Korea)
  • Year and Date: 2016-03-25
  • Int'l Joint Research / Invited
• [Presentation] Perspectives on therapeutic research for ALS (2016)
  • Author(s): 祖父江 元
  • Organizer: 3rd World Centenarians Initiative International Symposium on Amyotrophic Lateral Sclerosis
  • Place of Presentation: 千里ライフサイエンスセンター（大阪府豊中市）
  • Year and Date: 2016-02-19
  • Int'l Joint Research / Invited
• [Presentation] ALSの病態と治療：コホート研究から得られるもの (2015)
  • Author(s): 祖父江 元
  • Organizer: 第３回日本難病医療ネットワーク学会学術集会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2015-11-13
  • Invited
• [Presentation] 神経変性疾患のdisease-modifying therapy開発をめざして (2015)
  • Author(s): 祖父江 元
  • Organizer: 日本脳神経外科学会第74回学術総会
  • Place of Presentation: ロイトン札幌（北海道札幌市）
  • Year and Date: 2015-10-15
  • Invited
• [Presentation] Impact of aging on anatomical and functional human brain connectivity-toward early detection of dementia (2015)
  • Author(s): 祖父江 元
  • Organizer: 9th International Congress of the Asian Society Against Dementia (ASAD)
  • Place of Presentation: KKR熊本（熊本県熊本市）
  • Year and Date: 2015-09-15
  • Int'l Joint Research / Invited
• [Presentation] The future of clinical neuroscience (2015)
  • Author(s): 祖父江 元
  • Organizer: Brain connects 2015
  • Place of Presentation: 野依記念館（愛知県名古屋市）
  • Year and Date: 2015-07-31
  • Int'l Joint Research / Invited
• [Presentation] Novel imaging biomarker for early detection of AD (2015)
  • Author(s): 祖父江 元
  • Organizer: nd World Centenarian Initiative International Symposium on Alzheimer’s Disease Prevention Strategy
  • Place of Presentation: JA共済ビル カンファレンスホール（東京都千代田区）
  • Year and Date: 2015-06-27
  • Int'l Joint Research / Invited
• [Presentation] 神経変性疾患のdisease-modifying therapyをめざした我国初の医師主導治験の経験から (2015)
  • Author(s): 祖父江 元
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 朱鷺メッセ（新潟県新潟市）
  • Year and Date: 2015-05-20
  • Invited
• [Presentation] 神経変性疾患のdisease-modifying therapyへの展望 (2015)
  • Author(s): 祖父江 元
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-05-02
  • Invited
• [Presentation] 認知症制御へ向けた脳タンパク質老化と神経回路の可視化 (2015)
  • Author(s): 祖父江 元
  • Organizer: 第29回日本医学会総会2015関西
  • Place of Presentation: 京都国際会館（京都府京都市）
  • Year and Date: 2015-04-12
  • Invited