Understanding the common pathomechanisms underlying lysosomal and autophagic diseases

• Project/Area Number: 17H05088
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Pediatrics
• Research Institution: Kawasaki Medical School
• Principal Investigator: Otomo Takanobu 川崎医科大学, 医学部, 教授 (20742589)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥25,090,000 (Direct Cost: ¥19,300,000、Indirect Cost: ¥5,790,000); Fiscal Year 2019: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000); Fiscal Year 2018: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000); Fiscal Year 2017: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000)
• Keywords: リソソーム / オートファジー / 細胞内輸送 / リソソーム蓄積症 / ライソゾーム / リソソーム蓄積病

Outline of Final Research Achievements

Lysosomal disease is caused by impairment of lysosomal degradation system, but similar diseases are caused not only by reduction of lysosomal enzyme activity but also intracellular transport. We edited genes related to lysosomal functions or intracellular trafficking to prepare knock-out cell lines of these genes, and investigated cellular phenotypes. Our results showed that autophagy was significantly impaired only in a part of the lysosomal enzyme deficiency, and suggested that the mechanism of autophagy disorder among them was not uniform.

Academic Significance and Societal Importance of the Research Achievements

本研究により遺伝性希少疾患であるリソソーム病の疾患メカニズムの一端が明らかになり、今後のリソソームおよびリソソーム病研究を発展させるための細胞実験系や測定系が構築できたのは意義深い。また、リソソーム病に対する疾患特異的な治療法ではなく、共通の病態メカニズムを持つリソソーム病に対して疾患横断的に改善効果を与える手がかりとなる成果が得られ、今後本研究を発展させることで難病の治療法の開発につながることが期待される。

Research Products

• [Journal Article] Starvation-induced autophagy via calcium-dependent TFEB dephosphorylation is suppressed by Shigyakusan (2020)
  • Author(s): Ikari Sumiko、Lu Shiou-Ling、Hao Feike、Imai Kenta、Araki Yasuhiro、Yamamoto Yo-hei、Tsai Chao-Yuan、Nishiyama Yumi、Shitan Nobukazu、Yoshimori Tamotsu、Otomo Takanobu、Noda Takeshi
  • Journal Title: PLOS ONE Volume: 15 Issue: 3 Pages: 0230156-0230156
  • DOI: 10.1371/journal.pone.0230156
  • Peer Reviewed / Open Access
• [Journal Article] Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex. (2020)
  • Author(s): Kato K, Okuno Y, Vasilev FF, Otomo T, Oishi H, Muramatsu H, Kawano Y, Oka Y, Nakazawa Y, Ogi T, Takahashi Y, Saitoh S.
  • Journal Title: Journal of Medical genetics Volume: 57 Issue: 4 Pages: 245-253
  • DOI: 10.1136/jmedgenet-2019-106213
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mucopolysaccharidosis-Plus Syndrome (2020)
  • Author(s): Vasilev Filipp、Sukhomyasova Aitalina、Otomo Takanobu
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 2 Pages: 421-421
  • DOI: 10.3390/ijms21020421
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Understanding pathomechanisms of lysosomal storage disorders with cellular models using genome-editing technology (2019)
  • Author(s): Takanobu Otomo,Yukiko Kawakami, Filipp F. Vasilev, Junko Matsuda
  • Organizer: 米国先天代謝異常学会
  • Int'l Joint Research / Invited
• [Presentation] INVESTIGATION OF THE PROTEIN STABILITY OF VPS33A, A RESPONSIBLE MOLECULE FOR MPSPS (2019)
  • Author(s): Vasilev F., Kawakami Y., Otomo T.
  • Organizer: 日本ライソゾーム病研究会
• [Presentation] ライソゾーム関連遺伝子ノックアウト細胞における形態学的考察 (2019)
  • Author(s): 川上 由貴子、Filipp Vasilev、大友 孝信
  • Organizer: 日本ライソゾーム病研究会
• [Presentation] ゲノム編集技術を用いた、ライソゾーム病の包括的理解への挑戦 (2018)
  • Author(s): 大友孝信、川上由貴子、Filipp Vasilev、松田純子
  • Organizer: 第60回日本先天代謝異常学会
• [Presentation] Mucopolysaccharidosis-plus syndrome: report of two new cases (2018)
  • Author(s): Vasilev F., Kawakami Y., Gurinova E., Sukhomyasova A., Maksimova N., Matsuda J., Otomo T.
  • Organizer: 第60回日本先天代謝異常学会