exploration of CRAG gene therapy for neurodegenerative diseases

• Project/Area Number: 25460074
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: Inatome Ryoko 東京薬科大学, 生命科学部, 研究員 (90408691)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 神経変性疾患 / SRF / CRAG / 脊髄小脳変性症 / ALS / 遺伝子治療

Outline of Final Research Achievements

We previously demonstrated that CRAG facilitated the degradation of expanded polyglutamine protein via the nuclear ubiquitin-proteasome pathway and suggested that targeted delivery of CRAG may be useful as a gene therapy for neurodegenerative diseases such as polyglutamine diseases. However, the physiological relevance of CRAG in vivo is unknown. Here, we analyzed CRAG KO mice. Both whole-body and neuron-specific CRAG KO mice spontaneously developed severe neurodegenerative phenotypes cell death and lethality, within 1 month of birth. Kainic acid–induced c-fos expression was intensively suppressed in the hippocampus in these KO mice. Furthermore, CRAG interacted with ELK1, a coactivator of SRF, leading to ELK1-dependent SRF-c-fos induction. We conclude that CRAG plays a critical role in neuronal development and survival, at least in part through ELK1-dependent SRF-c-fos activation, and therefore suggesting the usefulness of CRAG gene therapy for neurodegenerative diseases.

Research Products

• [Journal Article] Roles of mitochondrial ubiquitin ligase MITOL/MARCH5 in mitochondrial dynamics and diseases (2014)
  • Author(s): Nagashima, S., Tokuyama, T., Yonashiro, R., Inatome, R., and Yanagi S.
  • Journal Title: J. Biochem Volume: 155 Issue: 5 Pages: 273-279
  • DOI: 10.1093/jb/mvu016
  • Peer Reviewed
• [Journal Article] MITOL regulates endoplasmic reticulum-mitochondria contacts via Mitofusin2. (2013)
  • Author(s): Sugiura, A., Nagashima, S., Tokuyama, T., Amo, T., Matsuki, Y., Ishido, S., Kudo, Y., McBride, H.M., Fukuda, T., Matsushita, T., Inatome, R., and C Yanagi, S.
  • Journal Title: Mol. Cell Volume: 51 Issue: 1 Pages: 1-15
  • DOI: 10.1016/j.molcel.2013.04.023
  • Peer Reviewed
• [Presentation] CRAGによって形成されるMitoTracker陽性の核内封入体の解析 (2015)
  • Author(s): 玉井 勇、長島 駿、福田敏史、稲留涼子、柳 茂
  • Organizer: BMB 2015第88回日本生化学会大会合同大会・第38回日本分子生物学会年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-03
• [Presentation] 神経回路形成関連分子CRAGによる生存シグナルと神経変性疾患への応用 (2014)
  • Author(s): 長島 駿、稲留涼子、柳 茂
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-18
• [Presentation] Role of mitochondrial ubiquitin ligase MITOL in mitochondrial dynamics and diseases
  • Author(s): 長島 駿, 杉浦 歩, 徳山剛士, 武田啓佑, 稲留涼子, 柳 茂
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜