Role of stress-induced transcription factor ATF3 on neurodegeneration of prion diseases
| Project/Area Number |
19H03119
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 42020:Veterinary medical science-related
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| Research Institution | Hokkaido University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2021: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2020: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
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| Keywords | プリオン / ATF3 / 神経細胞死 / フェロトーシス / プリオン病 / 神経変性疾患 / ストレス応答 / AFT3 / 小胞体ストレス / アデノ随伴ウイルスベクター / 神経細胞 / CRISPR/Cas9 |
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| Outline of Research at the Start |
プリオン病、アルツハイマー病など、タンパク質の異常凝集を伴う難治性の神経変性疾患では、小胞体ストレス、酸化ストレスなどに対するストレス応答が生じ、最終的には細胞機能が破綻して神経細胞死が生じる。神経細胞で生じる一連のストレス応答が明らかになれば、ストレス応答の制御による神経保護を標的とした治療法開発の道が開ける。研究代表者のグループは、プリオン感染マウスの視床の神経細胞で、ストレス誘導性の転写調節因子ATF3の発現が誘導され、神経細胞が脱落することを見出した。この現象を掘り下げ、プリオン病における神経変性機構の核心に迫る。
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| Outline of Final Research Achievements |
In this study, we analyzed the role of stress-inducible activating transcription factor 3 (ATF3) in the pathobiology of prion diseases. ATF3-positive cells were significantly increased in the thalamus and pontine nucleus of prion-infected mice, where neuronal cell death is well-observed, and around 80% of ATF-3 positive cells were identified as neurons. Apoptosis were not observed in the thalamus, where pronounced neuronal cell death occurred. The amount of GPx4 in the thalamus tended to decrease with prion infection. The 4-HNE, a marker of lipid peroxidation, was less accumulated in ATF3-positive neurons than ATF3-negative neurons. These results suggested that neurons in the thalamus die of ferroptosis and that induction of ATF3 expression may mitigate lipid peroxidation in the neurons and suppress ferroptosis.
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| Academic Significance and Societal Importance of the Research Achievements |
難治性神経変性疾患の一つであるプリオン病における神経細胞死に、脂質の過酸化が誘因となるフェロトーシスが関与する可能性を世界で初めて見いだしたことは、学術的に大きな意義がある。また、フェロトーシスの抑制が神経細胞死の抑制につながる可能性があり、治療法開発戦略の新たな治療標的となる点でも社会的な意義も大きいと考えられる。
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Report
(4 results)
Research Products
(25 results)
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[Journal Article] Refeeding activates neurons in the dorsomedial hypothalamus to inhibit food intake and promote positive valence2021
Author(s)
Daigo Imoto, Izumi Yamamoto, Hirokazu Matsunaga, Toya Yonekura, Ming-Liang Lee, Kan X Kato, Takeshi Yamasaki, Shucheng Xu, Taiga Ishimoto, Satoshi Yamagata, Ken-Ichi Otsuguro, Motohiro Horiuchi , Norifumi Iijima, Kazuhiro Kimura, Chitoku Toda
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Journal Title
Molecular Metabiolism
Volume: 54
Pages: 101366-101366
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Tracking and clarifying differential traits of the classical- and atypical L-type bovine spongiform encephalopathy prions after transmission from cattle to cynomolgus monkeys2019
Author(s)
Hagiwara, K., Yuko Sato, Y., Yamakawa, Y., Hara, H., Tobiume, M., Okemoto-Nakamura, Y., Sata, T., Horiuchi, M., Shibata, H., Ono, F.
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Journal Title
NAID
Related Report
Peer Reviewed
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[Journal Article] The first isolation and identification of canine parvovirus (CPV) type 2c variants during 2016 - 2018 genetic surveillance of dogs in Mongolia.2019
Author(s)
Uyangaa Temuujin, Ariunaa Tserendorj, Jumpei Fujiki, Yoshihiro Sakoda, Erdene-Ochir Tseren-Ochir, Masatoshi Okamatsu, Keita Matsuno, Tumenjargal Sharav, Motohiro Horiuchi, Takashi Umemura, Tungalag Chultemdorj.
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Journal Title
Infect. Genet. Evol.
Volume: 73
Pages: 936-942
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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