Clarification of mechanism of neurodegeneration in prion diseases by neuron-specific transcriptome analysis in brain

• Project/Area Number: 17K14954
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Hokkaido University
• Principal Investigator: Takeshi Yamasaki 北海道大学, 獣医学研究院, 助教 (70709881)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: プリオン病 / 神経変性 / トランスクリプトーム / 神経変性疾患 / 神経細胞死 / 脳神経疾患 / 神経科学

Outline of Final Research Achievements

Neurodegeneration in prion diseases is considered to be caused by generation of an abnormal isoform of prion protein (PrPSc) within neurons in the brains of animals affected by prions. In this study, we approached the molecular basis of mechanism of the neurodegeneration by comprehensive gene expression analysis of degenerating neurons in prion-infected mouse brains. Transcriptome analysis on the thalamus, where severe neuronal loss was observed, revealed that expression of apoptosis-related genes such as a stress-responsive transcription factor, ATF3, were up-regulated by prion-infection. The results suggest that neurodegeneration in prion diseases might be caused by the activation of signaling pathway involved in ATF3 molecules.

Academic Significance and Societal Importance of the Research Achievements

神経変性疾患の治療法開発のためには異常タンパクの増殖に起因する神経変性機構を解明することが最重要課題である。本研究で、プリオン病モデルマウスの脳内で変性過程にある神経細胞の遺伝子発現プロファイルが得られたことから、神経変性機構を理解する上で価値の高い情報を提供できた。また、プリオン感染マウスの脳内神経細胞で、アポトーシス関連因子の発現上昇を伴ってATF3が発現誘導されたことから、ATF3分子が変性過程にある神経細胞のマーカーとなることが示された。今後、ATF3分子を中心とした解析を行うことで、詳細な神経変性機構の解明、ひいてはATF3関連分子を標的とした治療法開発につながることが期待される。

Research Products

• [Journal Article] Retrograde transport by clathrin-coated vesicles is involved in intracellular transport of PrPSc in persistently prion-infected cells (2018)
  • Author(s): Yamasaki T, Suzuki A, Hasebe R, Horiuchi M.
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 12241-12241
  • DOI: 10.1038/s41598-018-30775-1
  • NAID: 120006539249
  • Peer Reviewed / Open Access
• [Journal Article] Flow cytometric detection of PrPSc in neurons and glial cells from prion-infected mouse brains (2018)
  • Author(s): Yamasaki T, Suzuki A, Hasebe R, Horiuchi M.
  • Journal Title: Journal of Virology Volume: 92 Issue: 1
  • DOI: 10.1128/jvi.01457-17
  • Peer Reviewed / Open Access
• [Presentation] 定型BSEおよび非定型BSEプリオンに感染したマウスの脳のトランスクリプトーム解析 (2018)
  • Author(s): 山崎剛士、岩丸祥史、鈴木章夫、長谷部理絵、堀内基広
  • Organizer: 第161回日本獣医学会学術集会
• [Presentation] Comparison of intracerebral spread of abnormal isoform of prion protein between three rodent prion strains (2018)
  • Author(s): Takeshi YAMASAKI, Akio SUZUKI, Rie HASEBE and Motohiro HORIUCHI
  • Organizer: Asian Pacific Prion Symposium 2018
  • Int'l Joint Research
• [Presentation] Comparison of intracerebral spread of abnormal isoform of prion protein between three rodent prion strains (2018)
  • Author(s): Takeshi YAMASAKI, Akio SUZUKI, Rie HASEBE and Motohiro HORIUCHI
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] Characterization of gene expression profiles in brains of mice infected with typical and atypical BSEs (2017)
  • Author(s): Takeshi Yamasaki, Yoshifumi Iwamaru, Yuichi Matsuura, Minori Kuroda, Rie Hasebe, Hiroyuki Okada and Motohiro Horiuchi
  • Organizer: Asia Pacific Prion Symposium 2017
  • Int'l Joint Research