Metabolic abnormality and pathogenesis of peroxisome biogenesis deficiency

• Project/Area Number: 19K07386
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Kyushu University
• Principal Investigator: Abe Yuichi 九州大学, 基幹教育院, 学術研究員 (00529092)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ペルオキシソーム / BDNF / 海馬 / 還元化 / 中枢神経系障害 / Pex2 / TrkB-T1 / 記憶障害 / カタラーゼ / グルタチオン / NADH / 大脳皮質 / 生理活性脂質

Outline of Research at the Start

細胞小器官の一つであるペルオキシソームの形成障害は大脳皮質の層構造破綻や炎症惹起など脳中枢神経系障害を導くが、その病態発症機構は明らかとなっていない。申請者は神経細胞遊走障害および炎症惹起の病態発症機構解明を目的とし、ペルオキシソーム形成異常症モデルマウスであるPex14ノックアウトマウスを用いて解析を行う。神経細胞遊走の解析には子宮内エレクトロポレーションを用い、炎症惹起に関しては炎症性サイトカインや脂質メディエーターを解析対象として研究を進める。

Outline of Final Research Achievements

Peroxisome is a subcellular organelle essential for various metabolic reactions. Peroxisome biogenesis disorders (PBDs) manifest as neurological deficits in the brain, including abnormal cerebellum development. We previously reported that an elevated level of brain-derived neurotrophic factor (BDNF) together with the enhanced expression of TrkB-T1, resulting in anormal development of Purkinje cells. In this research, we found that cytosolic reductive states caused by a mislocalized catalase in the peroxisome-deficient cells induce the elevation in BDNF secretion.
Peroxisomal functions in adulthood brain have been little investigated. To induce the peroxisome deficiency in adulthood brain, we established tamoxifen-inducible conditional Pex2-knockout mouse. Peroxisome deficiency in the conditional Pex2-knockout adult mouse brain induces the upregulated expression of BDNF and its inactive receptor TrkB-T1 in hippocampus, which notably results in memory disturbance.

Academic Significance and Societal Importance of the Research Achievements

ペルオキシソーム形成異常症に関して、我々はBDNF-TrkBシグナル伝達系異常を介した小脳形態障害の分子機構を世界で初めて解明してきた。本研究成果は、ペルオキシソーム欠損により誘発される細胞質還元化が及ぼすBDNF発現異常を明らかにし、未解明であったペルオキシソーム形成異常症の病態発症機構において、代謝障害を起因とする中枢神経系障害の分子機構を明らかにした重要な知見である。さらに、ペルオキシソーム機能が成体マウス海馬における記憶形成に必須であることを示し、成体脳における新たなペルオキシソーム機能を明らかにした重要な知見である。

Research Products

• [Int'l Joint Research] National Taiwan University(その他の国・地域（台湾）)
• [Int'l Joint Research] Galilee Medical Center(イスラエル)
• [Journal Article] <i>De novo</i> formation and maintenance of mammalian peroxisomes in the absence of PEX16 (2022)
  • Author(s): Yagita Yuichi、Abe Yuichi、Fujiki Yukio
  • Journal Title: Journal of Cell Science Volume: -
  • DOI: 10.1242/jcs.258377
  • Peer Reviewed
• [Journal Article] Identification of a Homozygous PEX26 Mutation in a Heimler Syndrome Patient (2021)
  • Author(s): Kim Youn Jung、Abe Yuichi、Kim Young-Jae、Fujiki Yukio、Kim Jung-Wook
  • Journal Title: Genes Volume: 12 Issue: 5 Pages: 646-646
  • DOI: 10.3390/genes12050646
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mammalian Homologue NME3 of DYNAMO1 Regulates Peroxisome Division (2020)
  • Author(s): Honsho Masanori、Abe Yuichi、Imoto Yuuta、Chang Zee-Fen、Mandel Hanna、Falik-Zaccai Tzipora C.、Fujiki Yukio
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 21 Pages: 8040-8040
  • DOI: 10.3390/ijms21218040
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Peroxisome deficiency impairs BDNF signaling and memory. (2020)
  • Author(s): Abe, Y., Nishimura, Y., Nakamura, K., Tamura, S., Honsho, M., Udo, H., Yamashita, T., and Fujiki, Y.
  • Journal Title: Front. Cell Dev. Biol. Volume: 8 Pages: 567017-567017
  • DOI: 10.3389/fcell.2020.567017
  • Peer Reviewed / Open Access
• [Journal Article] A peroxisome deficiency-induced reductive cytosol state up-regulates the brain-derived neurotrophic factor pathway (2020)
  • Author(s): Abe Yuichi、Honsho Masanori、Kawaguchi Ryoko、Matsuzaki Takashi、Ichiki Yayoi、Fujitani Masashi、Fujiwara Kazushirou、Hirokane Masaaki、Oku Masahide、Sakai Yasuyoshi、Yamashita Toshihide、Fujiki Yukio
  • Journal Title: Journal of Biological Chemistry Volume: - Issue: 16 Pages: 5321-5334
  • DOI: 10.1074/jbc.ra119.011989
  • Peer Reviewed / Open Access
• [Journal Article] Recent insights into peroxisome biogenesis and associated diseases (2020)
  • Author(s): *Fujiki, Y., Abe, Y., Imoto, Y., Tanaka, A.J., Okumoto, K., Honsho, M., Tamura, S., Miyata, N., Yamashita, T., Chung, W.K., and Kuroiwa, T.
  • Journal Title: J. Cell Sci. Volume: 133 Issue: 9 Pages: 236943-236943
  • DOI: 10.1242/jcs.236943
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Plasmalogen mediates integration of adherens junction (2019)
  • Author(s): Takahashi Takanori、Honsho Masanori、Abe Yuichi、Fujiki Yukio
  • Journal Title: The Journal of Biochemistry Volume: 166 Issue: 5 Pages: 423-432
  • DOI: 10.1093/jb/mvz049
  • NAID: 40022069621
  • Peer Reviewed / Open Access
• [Journal Article] Impaired plasmalogen synthesis dysregulates liver X receptor-dependent transcription in cerebellum (2019)
  • Author(s): Honsho Masanori、Dorninger Fabian、Abe Yuichi、Setoyama Daiki、Ohgi Ryohei、Uchiumi Takeshi、Kang Dongchon、Berger Johannes、Fujiki Yukio
  • Journal Title: The Journal of Biochemistry Volume: 166 Issue: 4 Pages: 353-361
  • DOI: 10.1093/jb/mvz043
  • NAID: 40022023663
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] ペルオキシソームの形態形成・分裂障害は リン脂質代謝異常をきたす (2021)
  • Author(s): 阿部雄一、藤木幸夫
  • Organizer: 第44回 日本分子生物学会
• [Presentation] ペルオキシソーム形成異常による小脳形態形成障害の病態発症機構 (2019)
  • Author(s): 阿部雄一、本庄雅則、伊藤竜太、藤谷昌司、中山啓子、大城遼平、中山敬一、山下俊英、藤木幸夫
  • Organizer: 第92回日本生化学会大会
• [Presentation] ペルオキシソーム欠損性アストロサイトにおける代謝障害とBDNF異常発現 (2019)
  • Author(s): 阿部 雄一, 本庄 雅則, 藤木 幸夫
  • Organizer: 第42回日本分子生物学会年会
• [Book] A mouse model system to study peroxisomal roles in neurodegeneration of peroxisome biogenesis disorders. In: Lizard, G. (ed.) Peroxisomes in Neurodegenerative Diseases, (2020)
  • Author(s): Abe, Y., Tamura, S., Honsho, M., and *Fujiki, Y.
  • Publisher: Springer Nature, Berlin Heidelberg New York.