Development of a histochemical analytical system for metabolic enzymes of novel brain glycosylated sterols

• Project/Area Number: 17KK0147
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Akiyama Hisako 国立研究開発法人理化学研究所, 脳神経科学研究センター, 研究員 (80623462)
• Project Period (FY): 2018 – 2020
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000)
• Keywords: ステロール / 糖化ステロール / 糖脂質 / グルコシルセラミド分解酵素 / 糖化

Outline of Final Research Achievements

The glucosylceramide-degrading enzyme (GBA) is responsible for the synthesis and degradation of newly found glycosylated sterols (SGs) in the brain. Using a library of GBA inhibitors, I found that GBA exerts various SG metabolic activities using the same active site. I succeeded in detecting SGs in a region of less than 1 mm2 recovered from mouse brain sections using mass spectrometry. Since active GBA can be visualized by fluorescence modified inhibitor, superimposition of the localization of enzyme activity and enzyme reaction products will enable histochemical localization analysis of SG metabolic activities of GBA.

Academic Significance and Societal Importance of the Research Achievements

SG群の代謝を担うGBAは、その機能不全がパーキンソン病や小脳失調などの難治性神経変性疾患の原因となる。本研究で提案したGBAのSG代謝活性の組織化学的局在解析法を用いることで、SG代謝が難治性神経変性疾患発症の新たな分子基盤となり得る可能性を検証できるようになるため、本研究成果の学術的・社会的意義は大きい。

Research Products

• [Int'l Joint Research] ライデン大学(オランダ) (2018)
  • Year and Date: 2018-08-01
• [Journal Article] Impact of GBA2 on neuronopathic Gaucher’s disease and α-synuclein accumulation in medaka (Oryzias latipes) (2021)
  • Author(s): Nakanishi, E., Uemura, N., Akiyama, H., Kinoshita, M., Sawamura, M., Taruno, Y., Yamakado, H., Matsuzawa, S., Takeda, S., Hirabayashi, Y., and Takahashi, R.
  • Journal Title: Molecular Brain Volume: 未定
  • Peer Reviewed
• [Journal Article] Glucocerebrosidases catalyze a transgalactosylation reaction that yields a newly-identified brain sterol metabolite, galactosylated cholesterol (2020)
  • Author(s): Akiyama, H., Ide, M., Nagatsuka, Y., Sayano, T., Nakanishi, E., Uemura, N., Yuyama, K., Yamaguchi, Y., Kamiguchi, H., Takahashi, R., Aerts, J. M. F. G., Greimel, P. and Hirabayashi, Y
  • Journal Title: Journal of Biological Chemistry Volume: 295 Issue: 16 Pages: 5257-5277
  • DOI: 10.1074/jbc.ra119.012502
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of β-glucosidase 2 in aberrant glycosphingolipid metabolism: model of glucocerebrosidase deficiency in zebrafish (2019)
  • Author(s): Lelieveld, L. T., Mirzaian, M, Kuo, C-L., Artola M., Ferraz, M. J., Peter, R. E. A., Akiyama, H., Greimel, P., van den Berg, R. J. B. H. N., Overkleeft, H. S., Boot, R. G., Meijer, A. H., and Aerts, J. M. F. G.
  • Journal Title: Journal of Lipid Research Volume: 60 Issue: 11 Pages: 1851-1867
  • DOI: 10.1194/jlr.ra119000154
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] GBA haploinsufficiency accelerates alpha-synuclein pathology with altered lipid metabolism in a prodromal model of Parkinson’s disease (2019)
  • Author(s): Ikuno Masashi、Yamakado Hodaka、Akiyama Hisako、Parajuli Laxmi Kumar、Taguchi Katsutoshi、Hara Junko、Uemura Norihito、Hatanaka Yusuke、Higaki Katsumi、Ohno Kousaku、Tanaka Masaki、Koike Masato、Hirabayashi Yoshio、Takahashi Ryosuke
  • Journal Title: Human Molecular Genetics Volume: 印刷中 Issue: 11 Pages: 1894-1904
  • DOI: 10.1093/hmg/ddz030
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Regulatory mechanism of sterylglucoside metabolism by glucocerebrosidase (2018)
  • Author(s): 秋山央子, 平林義雄
  • Journal Title: 生化学 Volume: 90 Issue: 3 Pages: 399-402
  • DOI: 10.14952/SEIKAGAKU.2018.900399
  • NAID: 40021622671
  • ISSN: 0037-1017
  • Year and Date: 2018-06-25
• [Journal Article] Pathological Structural Conversion of α-Synuclein Mediated by Glycosphingolipids (2018)
  • Author(s): 秋山央子
  • Journal Title: Trends in Glycoscience and Glycotechnology Volume: 30 Issue: 174 Pages: J85-J86
  • DOI: 10.4052/tigg.1813.6J
  • NAID: 130006744117
  • ISSN: 0915-7352, 1883-2113
  • Year and Date: 2018-05-25
• [Journal Article] Pathological Structural Conversion of α-Synuclein Mediated by Glycosphingolipids (2018)
  • Author(s): 秋山央子
  • Journal Title: Trends in Glycoscience and Glycotechnology Volume: 30 Issue: 174 Pages: E111-E112
  • DOI: 10.4052/tigg.1813.6E
  • NAID: 130006744118
  • ISSN: 0915-7352, 1883-2113
  • Year and Date: 2018-05-25
• [Presentation] 親水性相互作用クロマトグラフィー-質量分析法を用いた新規脳内糖脂質異性体の発見 (2021)
  • Author(s): 秋山央子
  • Organizer: 大阪大学蛋白質研究所セミナー
  • Invited
• [Presentation] Flexible activity of glucocerebrosidase generates a unique glycolipid metabolic network (2020)
  • Author(s): 秋山央子
  • Organizer: 第93回 日本生化学会大会
• [Presentation] グルコシルセラミド分解酵素はステロールとガラクトシルセラミド間のトランスガラクトシレーション反応を触媒する (2019)
  • Author(s): 秋山央子、井手三津子、Peter Greimel、Hans Aerts、上口裕之、平林義雄
  • Organizer: 第61回日本脂質生化学会
• [Presentation] Newly identified brain sterol metabolite glycosylated sterols are metabolized by β-glucocerebrosidase 1 and 2 in vivo (2019)
  • Author(s): Hisako Akiyama, Mitsuko Ide, Etsuro Nakanishi, Norihito Uemura, Yoshiki Yamaguchi, Hiroyuki Kamiguchi, Ryosuke Takahashi, Peter Greimel and Yoshio Hirabayashi
  • Organizer: 25th International Symposium on Glycoconjugates
  • Int'l Joint Research
• [Presentation] Glucocerebrosidase mediates a crosstalk between glycosphingolipid and sterol (2019)
  • Author(s): Hisako Akiyama
  • Organizer: Japan-Europe Workshop on Glycosphingolipids and Membrane Homeostasis
  • Int'l Joint Research
• [Presentation] グルコシルセラミド分解酵素による新規脳内ステロール代謝物・ステロール配糖体の代謝制御 (2019)
  • Author(s): 秋山央子、井手三津子、中西悦郎、上村紀仁、山口芳樹、Peter Greimel、上口裕之、高橋良輔、平林義雄
  • Organizer: 第92回 日本生化学会大会
• [Presentation] グルコシルセラミド分解酵素による脳内ステロール配糖体群の代謝制御 (2018)
  • Author(s): 秋山央子、井手三津子、佐矢野智子、中西悦郎、上村紀仁、Peter Greimel、高橋良輔、平林義雄
  • Organizer: 第60回日本脂質生化学会