Neurodegeneration induced by ectopic mitochondrial DNA

• Project/Area Number: 18H02716
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Niigata University
• Principal Investigator: Matsui Hideaki 新潟大学, 脳研究所, 教授 (60710853)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2018: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: ミトコンドリアDNA / パーキンソン病 / リソソーム / IFI16 / DNaseII / 神経変性

Outline of Final Research Achievements

In this study, we showed that mitochondrial DNA leaks into the cytoplasm in cultured cells and zebrafish that mimic the state of Parkinson's disease. It was also shown that the inflammatory reaction and neurodegeneration are improved by inhibiting the sensor of mitochondrial DNA leaked into the cytoplasm and promoting the degradation of cytoplasmic mitochondrial DNA. In addition, mitochondrial DNA leaked into the cytoplasm and its sensor IFI16 were accumulated in PD brains. These results suggest that cytoplasmic leakage of mitochondrial DNA may be an important cause of neurodegeneration in Parkinson's disease.

Academic Significance and Societal Importance of the Research Achievements

これまでに見いだされていなかったパーキンソン病の新たな病態を明らかにした研究である。細胞質に漏出したミトコンドリアDNAの分解、あるいはそのミトコンドリアDNAセンサーの阻害が、パーキンソン病の病態に立脚した新規治療法につながる可能性がある。またパーキンソン病以外の疾患、例えば心不全や肝臓線維化などでも同様のメカニズムが存在する可能性がある。パーキンソン病のさらなる解明や治療の開発と並行して、その他の疾患解析も検証を進める。

Research Products

• [Journal Article] Cytosolic dsDNA of mitochondrial origin induces cytotoxicity and neurodegeneration in cellular and zebrafish models of Parkinson’s disease. (2021)
  • Author(s): Matsui, H.*, Ito, J., Matsui, N., Uechi, T., Onodera, O., Kakita, A.
  • Journal Title: Nat. Commun. Volume: - Issue: 1 Pages: 3101-3101
  • DOI: 10.1038/s41467-021-23452-x
  • Peer Reviewed / Open Access
• [Journal Article] Degeneration of dopaminergic neurons and impaired intracellular trafficking in Atp13a2 deficient zebrafish (2020)
  • Author(s): Nyuzuki Hiromi、Ito Shinji、Nagasaki Keisuke、Nitta Yohei、Matsui Noriko、Saitoh Akihiko、Matsui Hideaki
  • Journal Title: IBRO Reports Volume: 9 Pages: 1-8
  • DOI: 10.1016/j.ibror.2020.05.002
  • Peer Reviewed / Open Access
• [Journal Article] 小型魚類を用いた医学研究 (2020)
  • Author(s): 松井秀彰*
  • Journal Title: 新潟県医師会報 Volume: 10 Pages: 2-6
• [Journal Article] Shrinkage of the myenteric neurons of the small intestine in patients with multiple system atrophy (2019)
  • Author(s): Ozawa Tetsutaro、Shimizu Hiroshi、Matsui Hideaki、Onodera Osamu、Kakita Akiyoshi
  • Journal Title: Autonomic Neuroscience Volume: 221 Pages: 102583-102583
  • DOI: 10.1016/j.autneu.2019.102583
  • Peer Reviewed
• [Journal Article] Age- and α-Synuclein-Dependent Degeneration of Dopamine and Noradrenaline Neurons in the Annual Killifish Nothobranchius furzeri (2019)
  • Author(s): Matsui Hideaki、Kenmochi Naoya、Namikawa Kazuhiko
  • Journal Title: Cell Reports Volume: 26 Issue: 7 Pages: 1727-1733.e6
  • DOI: 10.1016/j.celrep.2019.01.015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Parkinson’s disease pathogenesis from the viewpoint of small fish models (2017)
  • Author(s): Matsui Hideaki、Takahashi Ryosuke
  • Journal Title: J Neural Transm Volume: 125 Issue: 1 Pages: 25-33
  • DOI: 10.1007/s00702-017-1772-1
• [Presentation] Neurodegeneration induced by ectopic mtDNA. (2020)
  • Author(s): Matsui H.
  • Organizer: 第43回日本分子生物学会年会
  • Invited
• [Presentation] Age - and α-synuclein dependent degeneration of dopamine and noradrenaline neurons in the annual killifish Nothobranchius furzeri. (2019)
  • Author(s): Matsui H.
  • Organizer: 5th World Parkinson Congress
  • Int'l Joint Research
• [Presentation] Ectopic dsDNA of mitochondrial origin induces neurodegeneration. 異所性のミトコンドリアDNAが起こす神経変性. (2019)
  • Author(s): Matsui H.
  • Organizer: 第42回日本分子生物学会年会
  • Invited
• [Presentation] Cytosolic dsDNA of mitochondrial origin exerts cytotoxicity and neurodegeneration in PD (2019)
  • Author(s): Matsui H.
  • Organizer: 第42回神経科学学会
• [Presentation] Age - and α-synuclein dependent degeneration of dopamine and noradrenaline neurons in the annual killifish Nothobranchius furzeri. (2019)
  • Author(s): Matsui H.
  • Organizer: 第60回神経学会