The role of the endoplasmic reticulum in Mucopolysaccharidosis type II

• Project/Area Number: 17K10052
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Asahikawa Medical College (2018-2019); Hiroshima University (2017)
• Principal Investigator: Kanemoto Soshi 旭川医科大学, 医学部, 准教授 (90611913)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: ムコ多糖症 / ライソゾーム病 / 小胞体 / 小胞体関連分解 / イズロン酸-2-スルファターゼ

Outline of Final Research Achievements

Mucopolysaccharidosis type II (MPS II) is one of the lysosome diseases, which is designated as an intractable disease in Japan. Although the gene encoding iduronate 2-sulfatase　(IDS) is identified as the causative gene for MPS II, the molecular pathogenesis for MPS II is still not fully understood. In this study, causative mechanism was investigated with several mutant types of IDS gene overexpressing in the human cell line HeLa cells. As a result, normal type of IDS was transported from the endoplasmic reticulum (ER) to the lysosome in order to function as an enzyme which degrades glycosaminoglycan, while mutant IDS was accumulated in the ER and then was rapidly degraded by proteasome machinery. The inhibition of the degradation of mutant IDS by proteasome led to the recovery of the enzymatic activity of mutant IDS in part.

Academic Significance and Societal Importance of the Research Achievements

ムコ多糖症の治療法としては、対症療法に加えて、根治を目指すために酵素補充療法や造血幹細胞移植などの方法がとられる。しかし、根治療法にもそれぞれに利点と難点があることに加えて、中枢神経や骨など、効果が表れない組織もある。そのため、従来とは異なるアプローチによる治療戦略の確立が期待されている。本研究成果により、ハンター症候群の発症機構の一端を明らかにできた。プロテアソーム系を調節するという新たな切り口からのムコ多糖症治療戦略構築に貢献できる可能性が拓けた。

Research Products

• [Journal Article] Pathological changes in mice with long term cuprizone administration (2019)
  • Author(s): Nomura T, Bando Y, Nakazawa H, Kanemoto S, Yoshida S.
  • Journal Title: Neurochemistry International Volume: 126 Pages: 229-238
  • DOI: 10.1016/j.neuint.2019.03.018
  • Peer Reviewed
• [Journal Article] NFAT5 up-regulates expression of the kidney-specific ubiquitin ligase gene Rnf183 under hypertonic conditions in inner-medullary collecting duct cells. (2019)
  • Author(s): Maeoka Y, Wu Y, Okamoto T, Kanemoto S, Guo XP, Saito A, Asada R, Matsuhisa K, Masaki T, Imaizumi K, Kaneko M.
  • Journal Title: J Biol Chem. Volume: 294 Issue: 1 Pages: 101-115
  • DOI: 10.1074/jbc.ra118.002896
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Endoplasmic reticulum stress and diseases (2018)
  • Author(s): 金本聡自、今泉和則
  • Journal Title: 生化学 Volume: 90 Issue: 1 Pages: 51-59
  • DOI: 10.14952/SEIKAGAKU.2018.900051
  • ISSN: 0037-1017
  • Year and Date: 2018-02-25
• [Journal Article] Shutdown of ER-associated degradation pathway rescues functions of mutant iduronate 2-sulfatase linked to mucopolysaccharidosis type II. (2018)
  • Author(s): Osaki Y, Saito A, Kanemoto S, Kaneko M, Matsuhisa K, Asada R, Masaki T, Orii K, Fukao T, Tomatsu S, Imaizumi K
  • Journal Title: Cell Death Dis. Volume: 9 Issue: 8 Pages: 808-808
  • DOI: 10.1038/s41419-018-0871-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neuronal activity-dependent local activation of dendritic unfolded protein response promotes expression of brain-derived neurotrophic factor in cell soma. (2018)
  • Author(s): Saito A, Cai L, Matsuhisa K, Ohtake Y, Kaneko M, Kanemoto S, Asada R, Imaizumi K.
  • Journal Title: Journal of Neurochemistry Volume: 144 Issue: 1 Pages: 35-49
  • DOI: 10.1111/jnc.14221
  • Peer Reviewed / Open Access
• [Journal Article] Sec16A, a key protein in COPII vesicle formation, regulates the stability and localization of the novel ubiquitin ligase RNF183. (2018)
  • Author(s): Wu Y, Guo XP, Kanemoto S, Maeoka Y, Saito A, Asada R, Matsuhisa K, Ohtake Y, Imaizumi K, Kaneko M.
  • Journal Title: PLoS One Volume: 13 Issue: 1 Pages: e0190407-e0190407
  • DOI: 10.1371/journal.pone.0190407
  • Peer Reviewed / Open Access
• [Journal Article] Axonal Activation of the Unfolded Protein Response Promotes Axonal Regeneration Following Peripheral Nerve Injury. (2018)
  • Author(s): Ohtake Y, Matsuhisa K, Kaneko M, Kanemoto S, Asada R, Imaizumi K, Saito A.
  • Journal Title: Neuroscience Volume: 375 Pages: 34-48
  • DOI: 10.1016/j.neuroscience.2018.02.003
  • Peer Reviewed / Open Access
• [Journal Article] ER Stress and Disease: Toward Prevention and Treatment (2017)
  • Author(s): Kaneko M, Imaizumi K, Saito A, Kanemoto S, Asada R, Matsuhisa K, Ohtake Y.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 40 Issue: 9 Pages: 1337-1343
  • DOI: 10.1248/bpb.b17-00342
  • NAID: 130006038767
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed
• [Presentation] 小胞体関連分解によるムコ多糖症原因分子イズロン酸-2-スルファターゼの活性化抑制機構 (2017)
  • Author(s): 尾﨑陽介、金本聡自、齋藤敦、今泉和則
  • Organizer: 日本生化学会 中国・四国支部会