Elucidation of mechanisms of neurodegeneration by reversible regulation of mitochondrial dynamics

• Project/Area Number: 18K06203
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 44010:Cell biology-related
• Research Institution: University of Tsukuba
• Principal Investigator: ISHIKAWA Kaori 筑波大学, 生命環境系, 助教 (40734827)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: ミトコンドリア / MFN2 / 神経変性疾患 / 病態モデル / 神経変性 / 誘導発現 / モデルマウス / Tet-off / ミトコンドリアダイナミクス / 行動異常 / 認知機能 / 運動障害 / 神経変性疾患モデル / ミトコンドリア・ダイナミクス / Mfn2

Outline of Final Research Achievements

Using a mouse model in which a dominant-negative mutant of a mitochondrial fusion factor MFN2 can be expressed inducibly and neuron specifically, pathological differences caused by changing the timing and duration of expression of the mutant MFN2 were compared. The results showed that there was a significant difference in the pathology depending on the timing and duration of expression of the mutant MFN2, even though it was the same mutant of the same gene.

Academic Significance and Societal Importance of the Research Achievements

神経変性疾患は、ヒトの病態進行を忠実に再現できる動物モデルに乏しく、これが病態発症機構の解明や有効な治療薬開発を困難にしている一因である。脳機能が一通り成熟する生後8週齢以降に変異型MFN2を継続的に発現させたマウスの病態は、成熟期以降に誘導される進行性の神経変性と、それに伴う行動異常や顕著な認知機能の低下であり、この病態進行はヒトの神経変性疾患とよく似ていた。このことから、神経変性疾患を模倣するモデルの樹立には、病因因子のOnsetの時期を考慮することが重要であることが伺える。本成果は、神経変性疾患領域における有効な病態モデル構築において重要な知見になると考えられる。

Research Products

• [Journal Article] Neuronal degeneration and cognitive impairment can be prevented via the normalization of mitochondrial dynamics (2021)
  • Author(s): Ishikawa Kaori、Yamamoto Satoshi、Hattori Satoko、Nishimura Naoya、Matsumoto Hirokazu、Miyakawa Tsuyoshi、Nakada Kazuto
  • Journal Title: Pharmacological Research Volume: 163 Pages: 105246-105246
  • DOI: 10.1016/j.phrs.2020.105246
  • Peer Reviewed
• [Journal Article] Attempts to understand the mechanisms of mitochondrial diseases: The reverse genetics of mouse models for mitochondrial disease (2021)
  • Author(s): Ishikawa Kaori、Nakada Kazuto
  • Journal Title: Biochimica et Biophysica Acta (BBA) - General Subjects Volume: 1865 Issue: 3 Pages: 129835-129835
  • DOI: 10.1016/j.bbagen.2020.129835
  • Peer Reviewed
• [Journal Article] Pharmacokinetic and pharmacodynamic modeling of the metastin/kisspeptin analog, TAK‐448, for its anti‐tumor efficacy in a rat xenograft model (2020)
  • Author(s): Kogame Akifumi、Ishikawa Kaori、DeJongh Joost、Tagawa Yoshihiko、Matsui Hisanori、Moriya Yuu、Kondo Takahiro、Asahi Satoru
  • Journal Title: Biopharmaceutics & Drug Disposition Volume: 41 Issue: 7 Pages: 283-294
  • DOI: 10.1002/bdd.2245
  • Peer Reviewed
• [Journal Article] Acquired expression of mutant Mitofusin 2 causes progressive neurodegeneration and abnormal behavior (2019)
  • Author(s): Ishikawa K, Yamamoto S, Hattori S, Nishimura N, Tani H, Mito T, Matsumoto H, Miyakawa T, Nakada K
  • Journal Title: The Journal of Neuroscience Volume: 39 Issue: 9 Pages: 1588-1604
  • DOI: 10.1523/jneurosci.2139-18.2018
  • Peer Reviewed
• [Journal Article] Concentration of mitochondrial DNA mutations by cytoplasmic transfer from platelets to cultured mouse cells. (2019)
  • Author(s): Ishikawa K, Kobayashi K, Yamada A, Umehara M, Oka T, Nakada K.
  • Journal Title: PLoS ONE Volume: 14 Issue: 3 Pages: 0213283-0213283
  • DOI: 10.1371/journal.pone.0213283
  • NAID: 120007133505
  • Peer Reviewed / Open Access
• [Journal Article] Disruption of the mouse Shmt2 gene confers embryonic anaemia via foetal liver-specific metabolomic disorders (2019)
  • Author(s): Tani Haruna、Mito Takayuki、Velagapudi Vidya、Ishikawa Kaori、Umehara Moe、Nakada Kazuto、Suomalainen Anu、Hayashi Jun-Ichi
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 16054-16054
  • DOI: 10.1038/s41598-019-52372-6
  • NAID: 120007132907
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mito-mice∆ and mitochondrial DNA mutator mice as models of human osteoporosis caused not by aging but by hyperparathyroidism (2018)
  • Author(s): Mito Takayuki、Tani Haruna、Suzuki Michiko、Ishikawa Kaori、Nakada Kazuto、Hayashi Jun-Ichi
  • Journal Title: Experimental Animals Volume: 67 Issue: 4 Pages: 509-516
  • DOI: 10.1538/expanim.18-0060
  • ISSN: 0007-5124, 1341-1357, 1881-7122
  • Peer Reviewed
• [Journal Article] Mice deficient in the Shmt2 gene have mitochondrial respiration defects and are embryonic lethal. (2018)
  • Author(s): Tani H, Ohnishi S, Shitara H, Mito T, Yamaguchi M, Yonekawa H, Hashizume O, Ishikawa K, Nakada K, Hayashi JI.
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 425-425
  • DOI: 10.1038/s41598-017-18828-3
  • NAID: 120007134501
  • Peer Reviewed / Open Access
• [Presentation] 突然変異型MFN2の時期特異的発現調節による神経変性の病態比較 (2020)
  • Author(s): 石川香、山本智、服部聡子、西村尚也、松本寛和、宮川剛、中田和人
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] 突然変異型MFN2の神経特異的な誘導性発現による病態の評価 (2020)
  • Author(s): 石川香
  • Organizer: 2019年度文部科学省新学術領域研究 学術研究支援基盤形成 先端モデル動物支援プラットフォーム成果発表会
  • Invited
• [Presentation] Human neurodegenerative disease-like phenotypes induced by acquired expression of mutant MFN2 in mice. (2019)
  • Author(s): 1.Kaori Ishikawa, Satoshi Yamamoto, Satoko Hattori, Naoya Nishimura, Haruna Tani, Hirokazu Matsumoto, Tsuyoshi Miyakawa, and Kazuto Nakada
  • Organizer: The 16th Conference of Asian Society for Mitochondrial Research and Medicine [ASMRM] and The 19th Conference of Japan Society for Mitochondrial Research and Medicine [J-mit]
  • Int'l Joint Research
• [Presentation] Generation and analysis of trans-mitochondrial mice carrying mtDNA with a point mutation in tRNALeu(UUR) gene. (2019)
  • Author(s): 2.Haruna Tani, Kaori Ishikawa, Jun-Ichi Hayashi, Kazuto Nakada
  • Organizer: The 16th Conference of Asian Society for Mitochondrial Research and Medicine [ASMRM] and The 19th Conference of Japan Society for Mitochondrial Research and Medicine [J-mit]
  • Int'l Joint Research
• [Presentation] Progressive neurodegeneration and abnormal behavior were caused by acquired expression of mutant Mitofusin 2 in neurons. (2019)
  • Author(s): 34.Kaori Ishikawa, Satoshi Yamamoto, Satoko Hattori, Naoya Nishimura, Takayuki Mito, Hirokazu Matsumoto, Tsuyoshi Miyakawa, Kazuto Nakada
  • Organizer: The Cold Spring Harbor Asia conference on Mitochondria and Metabolism in Health and Disease
  • Int'l Joint Research / Invited
• [Presentation] マウス培養細胞は組織よりも高い割合のミトコンドリアDNA突然変異を許容できる (2018)
  • Author(s): 石川香、小林晃平、山田亮仁、梅原萌、岡敏彦、中田和人
  • Organizer: 第18回日本ミトコンドリア学会年会
• [Presentation] The D210V mutation of Mfn2 in neurons induces different pathologies in severity depends on its expression timing (2018)
  • Author(s): Kaori Ishikawa
  • Organizer: Keystone Symposia “Mitochondrial Biology”
  • Int'l Joint Research
• [Presentation] The importance of Mfn2 in neuronal function from juvenile to adult phase (2018)
  • Author(s): Kaori Ishikawa, Satoshi Yamamoto, Satoko Hattori, Naoya Nishimura, Takayuki Mito, Hirokazu Matsumoto, Tsuyoshi Miyakawa, Kazuto Nakada
  • Organizer: International YoungMito “The 1st International Mitochondria Meeting for Young Scientists”
  • Int'l Joint Research
• [Presentation] Progressive neurodegeneration and abnormal behavior were caused by acquired expression of mutant Mitofusin 2 in neurons (2018)
  • Author(s): Kaori Ishikawa, Satoshi Yamamoto, Satoko Hattori, Naoya Nishimura, Takayuki Mito, Hirokazu Matsumoto, Tsuyoshi Miyakawa, Kazuto Nakada
  • Organizer: The 41st Annual Meeting of the Molecular Biology Society of Japan
  • Int'l Joint Research / Invited
• [Remarks] 筑波大学生命環境系 中田・石川研究室HP
  • URL: https://www.biol.tsukuba.ac.jp/nakada_ishikawa/index.html
• [Remarks] 筑波大学生命環境系 中田・石川研究室
  • URL: http://www.biol.tsukuba.ac.jp/nakada_ishikawa/index.html
• [Remarks] 筑波大学生命環境系 中田・石川研HP
  • URL: http://www.biol.tsukuba.ac.jp/nakada_ishikawa/index.html
• [Remarks] 筑波大学 注目の研究
  • URL: http://www.tsukuba.ac.jp/attention-research/r201903291000.html