Establishment of a novel animal model of ALS expressing GGGGCC repeat RNA in Drosophila, and analyses of its pathogenic mechanisms

• Project/Area Number: 25860733
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: UEYAMA Morio 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 (20386593)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 脳・神経 / 脳神経疾患 / RNA / 遺伝子 / ショウジョウバエ / RNA結合蛋白質

Outline of Final Research Achievements

Amyotrophic lateral sclerosis (ALS) is a devastating disease with movement disorder characterized by degeneration and loss of motor neurons. Recently, an abnormal expansion of GGGGCC repeat in the untranslated region of C9ORF72 gene has been found to be responsible for familial ALS. However, its molecular mechanism leading to ALS pathogenesis remains unclear. To elucidate the pathogenic mechanisms of ALS caused by an expanded repeat, we had established a novel Drosophila model of ALS expressing the GGGGCC repeat RNA. Next, we found that one of the causative gene of ALS, FUS genetically interacts with GGGGCC repeat, indicating that FUS contributes to pathogenic mechanisms of ALS related to GGGGCC repeat expansion.

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] 神経変性疾患への新しい視点 -プリオン仮説- D.タウ蛋白による前頭側頭葉変性症 (FTLD-Tau) 3.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 Neurosci. Volume: 33 Pages: 312-314
• [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
• [Presentation] GGGGCCリピートRNAを発現する新規ALSモデルショウジョウバエの樹立と病態解析 (2014)
  • Author(s): 上山盛夫、石黒太郎、藤掛伸宏、今野卓哉、小山哲秀、小野寺理、和田圭司、永井義隆
  • Organizer: 日本遺伝学会第86回大会
  • Place of Presentation: 長浜
  • Year and Date: 2014-09-17 – 2014-09-19