Study on the mechanism of inflammation in the CNS of gangliosidosis

• Project/Area Number: 17K10057
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Yokohama City University
• Principal Investigator: YAMANAKA Shoji 横浜市立大学, 附属病院, 准教授 (80264604)
• Co-Investigator(Kenkyū-buntansha): 山口 章 横浜市立大学, 医学研究科, 客員講師 (20381585)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: ガングリオシドーシス / サンドホフ病 / ライソソーム病 / TLR / ライソゾーム蓄積病 / GM2ガングリオシドーシス / TLR4 / 炎症反応 / ライソソーム蓄積病 / 炎症 / 自然免疫 / 遺伝病 / ガングリオシド / マイクログリア / ライソゾーム病

Outline of Final Research Achievements

Sandhoff disease (SD), which is one of the lysosomal storage diseases, is a pathological condition in which undegraded glycolipids accumulate in the central nervous system(CNS) due to a congenital deficiency of β-hexosaminidases A and B, which reside in lysosome. As a result of accumulation of the undegraded substances, neuronal disturbance progress.
However, in our study, the progression of SD pathology is not only caused by the accumulation of the glycolipids in the CNS, but also caused by the autoantibody formation because the undegraded substances potentially become autoantigen. In addition, the accumulation found in this study directly stimulates astrocytes via Toll-like receptors (TLRs) 2,4, and TNF-α and IL-1β are produced in the CNS. It was confirmed that an inflammatory reaction was triggered, and the condition progressed.

Academic Significance and Societal Importance of the Research Achievements

これまでサンドホフ病を含むGM2ガングリオシドーシスは先天的にライソソーム酵素の欠損により、その代謝物である糖脂質が中枢神経系に蓄積し、どの様なメカニズムで病態を進行させるかは解明されていなかった。
本研究の結果、サンドホフ病ではその病態の進行に蓄積物がアストロサイトを直接刺激し、炎症性サイトカインが産生されることによる中枢神経系での炎症反応が深く関与していること見出された。
現在遺伝子の欠損病であるサンドホフ病は、根本的な治療法は無く、症状による対症療法のみとなっているが、本研究の結果により、炎症反応を軽減させる事により、病勢の進行を遅らせ、将来的には治療の開発に役立つものと考えられる。

Research Products

• [Journal Article] IDH-Mutant Astrocytoma With Chromosome 19q13 Deletion Manifesting as an Oligodendroglioma-Like Morphology. (2021)
  • Author(s): Miyake Y, Fujii K, Nakamaura T, Ikegaya N, Matsushita Y, Gobayashi Y, Iwashita H, Udaka N, Kumagai J, Murata H, Takemoto Y, Yamanaka S, Ichimura K, Tateishi K, Yamamoto T.
  • Journal Title: J Neuropathol Exp Neurol. Volume: 80 Issue: 3 Pages: 247-253
  • DOI: 10.1093/jnen/nlaa161
  • Peer Reviewed / Open Access
• [Journal Article] Quantitative multiparametric magnetic resonance imaging can aid non-alcoholic steatohepatitis diagnosis in a Japanese cohort. (2021)
  • Author(s): Imajo K, Tetlow L, Dennis A, Shumbayawonda E, Mouchti S, Kendall TJ, Fryer E, Yamanaka S, Honda Y, Kessoku T, Ogawa Y, Yoneda M, Saito S, Kelly C, Kelly MD, Banerjee R, Nakajima A.
  • Journal Title: World J Gastroenterol. Volume: 27 Issue: 7 Pages: 609-623
  • DOI: 10.3748/wjg.v27.i7.609
  • Peer Reviewed / Open Access
• [Journal Article] Pathogenic UBA1 variants associated with VEXAS syndrome in Japanese patients with relapsing polychondritis (2021)
  • Author(s): Tsuchida Naomi、Kunishita Yosuke、Uchiyama Yuri、Kirino Yohei、Enaka Makiko、Yamaguchi Yukie、Taguri Masataka、Yamanaka Shoji、Takase-Minegishi Kaoru、Yoshimi Ryusuke、Fujii Satoshi、Nakajima Hideaki、Matsumoto Naomichi
  • Journal Title: Annals of the Rheumatic Diseases Volume: - Issue: 8 Pages: 1057-1061
  • DOI: 10.1136/annrheumdis-2021-220089
  • Peer Reviewed
• [Journal Article] Effect of Yuzu (Citrus junos) Seed Limonoids and Spermine on Intestinal Microbiota and Hypothalamic Tissue in the Sandhoff Disease Mouse Model. (2021)
  • Author(s): Minamisawa M, Suzumura T, Bose S, Taniai T, Kawai G, Suzuki K, Yamaguchi A, Yamanaka S.
  • Journal Title: Med Sci (Basel). Volume: 9 Issue: 1 Pages: 17-17
  • DOI: 10.3390/medsci9010017
  • Peer Reviewed / Open Access
• [Journal Article] A Hyperactive RelA/p65-Hexokinase 2 Signaling Axis Drives Primary Central Nervous System Lymphoma (2020)
  • Author(s): Tateishi Kensuke、Miyake Yohei、Kawazu Masahito、Sasaki Nobuyoshi、Nakamura Taishi、Sasame Jo、Yoshii Yukie、Ueno Toshihide、Miyake Akio、Matsushita Yuko、Shiba Norio、Udaka Naoko、Ohki Kentaro、Fink Alexandria L.、Tummala Shilpa S.、Natsumeda Manabu、Miller Julie J.、Fujii Yukihiko、et al
  • Journal Title: Cancer Research Volume: 80 Issue: 23 Pages: 5330-5343
  • DOI: 10.1158/0008-5472.can-20-2425
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] BRAF V600E mutation mediates FDG-methionine uptake mismatch in polymorphous low-grade neuroepithelial tumor of the young (2020)
  • Author(s): Tateishi Kensuke、Ikegaya Naoki、Udaka Naoko、Sasame Jo、Hayashi Takahiro、Miyake Yohei、Okabe Tetsuhiko、Minamimoto Ryogo、Murata Hidetoshi、Utsunomiya Daisuke、Yamanaka Shoji、Yamamoto Tetsuya
  • Journal Title: Acta Neuropathologica Communications Volume: 8 Issue: 1 Pages: 139-139
  • DOI: 10.1186/s40478-020-01023-3
  • Peer Reviewed / Open Access
• [Journal Article] Pembrolizumab-induced secondary sclerosing cholangitis in a non-small cell lung cancer patient (2020)
  • Author(s): Matsumoto S, Watanabe K, Kobayashi N, Irie K, Yamanaka S, Kaneko T.
  • Journal Title: Respirol Case Rep. Volume: 8 Issue: 5
  • DOI: 10.1002/rcr2.560
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of PDX‐derived salivary adenoid cystic carcinoma cell lines using organoid culture method (2020)
  • Author(s): Takada Kentaro、Aizawa Yoshihiro、Sano Daisuke、Okuda Ryo、Sekine Keisuke、Ueno Yasuharu、Yamanaka Shoji、Aoyama Jun、Sato Kaname、Kuwahara Tatsu、Hatano Takashi、Takahashi Hideaki、Arai Yasuhiro、Nishimura Goshi、Taniguchi Hideki、Oridate Nobuhiko
  • Journal Title: International Journal of Cancer Volume: 148 Issue: 1 Pages: 193-202
  • DOI: 10.1002/ijc.33315
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Actinomycotic osteomyelitis with proliferative periostitis arising in the mandibular ramus: an unusual case with spontaneous bone regeneration after coronoidectomy (2020)
  • Author(s): Iwai Toshinori、Ohashi Nobuhide、Sugiyama Satomi、Kitajima Hiroaki、Hirota Makoto、Yamanaka Shoji、Mitsudo Kenji
  • Journal Title: Oral Radiology Volume: 37 Issue: 1 Pages: 137-145
  • DOI: 10.1007/s11282-020-00462-x
  • Peer Reviewed
• [Journal Article] Clinical features of isolated proximal‐type immunoglobulin G4‐related sclerosing cholangitis (2019)
  • Author(s): Takagi Yuri、Kubota Kensuke、Takayanagi Takuya、Kurita Yusuke、Ishii Ken、Hasegawa Sho、Iwasaki Akito、Sato Takamitsu、Fujita Yuji、Kato Shingo、Kagawa Koichi、Watanabe Seitaro、Sekino Yusuke、Hosono Kunihiro、Matsuhashi Nobuyuki、Yamanaka Shoji、Iwao Toshiyasu、Yoshida Koji、Nakajima Atsushi
  • Journal Title: Digestive Endoscopy Volume: 31 Issue: 4 Pages: 422-430
  • DOI: 10.1111/den.13320
  • Peer Reviewed
• [Journal Article] Genome-wide DNA Methylation Profiling Shows Molecular Heterogeneity of Anaplastic Pleomorphic Xanthoastrocytoma (2019)
  • Author(s): Nakamura T, Fukuoka K, Nakano Y, Yamasaki K, Matsushita Y, Yamashita S, Ikeda J, Udaka N, Tanoshima R, Shiba N, Tateishi K, Yamanaka S, Yamamoto T, Hirato J, Ichimura K.
  • Journal Title: Cancer Sci. Volume: 110 Issue: 2 Pages: 828-832
  • DOI: 10.1111/cas.13903
  • Peer Reviewed / Open Access
• [Journal Article] Multicenter experience with large panel next-generation sequencing in patients with advanced solid cancers in Japan. (2019)
  • Author(s): Kato S, Hayashi T, Suehara Y, Hamanoue H, Yamanaka S, Ichikawa Y, Higurashi T, Ohashi K, Yamaguchi S, Nozaki Y, Terao Y, Saito T.
  • Journal Title: Jpn J Clin Oncol Volume: 49(2) Issue: 2 Pages: 174-182
  • DOI: 10.1093/jjco/hyy173
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Outcomes of surgery for 2010 WHO classification-based intraductal papillary neoplasm of the bile duct: Case?control study of a single Japanese institution's experience with special attention to mucin expression patterns (2019)
  • Author(s): Harada Fumi、Matsuyama Ryusei、Mori Ryutaro、Kumamoto Takafumi、Morioka Daisuke、Taguri Masataka、Yamanaka Shoji、Endo Itaru
  • Journal Title: European Journal of Surgical Oncology Volume: 45 Issue: 5 Pages: 761-768
  • DOI: 10.1016/j.ejso.2018.10.532
• [Journal Article] Improvement in dysmyelination by the inhibition of microglial activation in a mouse model of Sandhoff disease (2018)
  • Author(s): Ogawa Y, Irisa M, Sano T, Yanagi Y, Furusawa E, Saito T, Yamanaka S, Itoh K, Sakuraba H, Oishi K
  • Journal Title: Neuroreport Volume: 29 Issue: 11 Pages: 962-967
  • DOI: 10.1097/wnr.0000000000001060
  • Peer Reviewed / Open Access
• [Journal Article] FcRγ-dependent immune activation initiates astrogliosis during the asymptomatic phase of Sandhoff disease model mice (2017)
  • Author(s): Ogawa Y, Sano T, Irisa M, Kodama T, Saito T, Furusawa E, Kaizu K, Yanagi Y, Tsukimura T, Togawa T, Yamanaka S, Itoh K, Sakuraba H, Oishi K
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 40518
  • DOI: 10.1038/srep40518
  • NAID: 120006535048
  • URL: https://tokushima-u.repo.nii.ac.jp/records/2005581
  • Peer Reviewed / Open Access / Acknowledgement Compliant