Development of an analytical platform for novel brain glycosylated sterols toward applying for the treatment of neurodegenerative diseases

• Project/Area Number: 17K15608
• Research Category: Grant-in-Aid for Young Scientists (B)
• 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): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 糖脂質 / 糖化ステロール / グルコシルセラミド分解酵素 / コレステロール / グルコシルセラミド / パーキンソン病 / GBA

Outline of Final Research Achievements

I developed an analytical method specific to novel glycosylated sterols that we discovered in the brain, and analyzed the metabolic pathways and physiological functions of the glycosylated sterols. The results showed that the metabolism of the glycosylated sterols is mediated by glucosylceramide-degrading enzymes (GBA). In addition, the expression of glycosylated sterols was altered in the brains of mouse model of Parkinson's disease with impaired GBA function.

Academic Significance and Societal Importance of the Research Achievements

脳内新規糖化ステロール群の代謝を担うことが明らかになったグルコシルセラミド分解酵素は、その機能不全がパーキンソン病や小脳失調などの神経変性疾患の原因となる。本研究で開発した分析法を用いることで、糖化ステロール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り、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)
• [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] 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
• [Journal Article] A novel function for glucocerebrosidase as a regulator of sterylglucoside metabolism (2017)
  • Author(s): Akiyama H. and Hirabayashi Y
  • Journal Title: Biochim. Biophys. Acta. Volume: 1861 Issue: 10 Pages: 2507-2514
  • DOI: 10.1016/j.bbagen.2017.06.003
  • Peer Reviewed
• [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] 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] 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
• [Presentation] Identification of novel brain sterol metabolite galactosylated cholesterol synthesized by glucocerebrosidases (2018)
  • Author(s): Hisako Akiyama, Yasuko Nagatsuka, Tomoko Sayano, Mitsuko Ide, Yoshiki Yamaguchi, Peter Greimel, Yoshio Hirabayashi
  • Organizer: Glycolipid & Sphingolipid Biology, Gordon Research Conference
  • Int'l Joint Research
• [Presentation] 脳における多様なステリルグリコシド：コレステロールおよび植物ステロール配糖体の完全構造決定 (2017)
  • Author(s): 秋山央子、中嶋和紀、伊藤喜之、佐矢野智子、大橋陽子、山口芳樹、Peter Greimel、平林義雄
  • Organizer: 第65回質量分析総合討論会
• [Presentation] ステロールとスフィンゴ脂質の代謝的クロストークが生み出す新たな糖脂質 (2017)
  • Author(s): 秋山央子、中嶋和紀、佐矢野智子、大橋陽子、山口芳樹、Peter Greimel、平林義雄
  • Organizer: 第59回日本脂質生化学会
• [Presentation] 新規脳内糖化ステロール群の発見：多様なステロールおよび糖鎖構造 (2017)
  • Author(s): 秋山央子、中嶋和紀、佐矢野智子、長塚靖子、山口芳樹、Peter Greimel、平林義雄
  • Organizer: 第36回日本糖質学会