Molecular mechanism of conformational alteration in SOD1 and its disruption in the pathogenesis of ALS

• Project/Area Number: 18K15358
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: The University of Tokyo
• Principal Investigator: Fujisawa Takao 東京大学, 大学院薬学系研究科(薬学部), 助教 (50636644)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
• Keywords: ALS / SOD1 / 亜鉛

Outline of Final Research Achievements

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with no cure. SOD1, one of the causative genes in familial ALS, is structurally altered by ALS-linked genetic mutation and exerts cytotoxicity. We have previously reported that wild-type SOD1 (SOD1 WT) also adopts a mutant-like conformation under stress conditions, but the detailed molecular mechanism and its involvement in ALS have not been clarified. In this study, we focused on mutant-like SOD1 and performed comprehensive studies on its subcellular localization, binding factors, post-translational modifications, and degradation systems. We elucidated the molecular basis of conformational alteration in SOD1 WT under stress conditions.

Academic Significance and Societal Importance of the Research Achievements

変異型SOD1がALSの原因になることはよく知られているが、ストレス条件下で変異型様に構造が変化した野生型SOD1のALSへの関与ついては不明な点が多い。本研究で明らかにした野生型SOD1の構造変化の分子基盤に関する基礎的知見は、SOD1遺伝子変異によらない家族性ALSおよび孤発性ALSにおけるSOD1の病態生理学的意義の解明や創薬ターゲットの発見につながると期待される。

Research Products

• [Journal Article] Elevated placental histone H3K4 methylation via upregulated histone methyltransferases SETD1A and SMYD3 in preeclampsia and its possible involvement in hypoxia-induced pathophysiological process. (2021)
  • Author(s): H. Matsui, T. Iriyama, S. Sayama, N. Inaoka, K. Suzuki, M. Yoshikawa, M. Ichinose, K. Sone, K. Kumasawa, T. Nagamatsu, T. Fujisawa, I. Naguro, H. Ichijo, T. Fujii, Y. Osuga
  • Journal Title: Placenta Volume: 115 Pages: 60-69
  • DOI: 10.1016/j.placenta.2021.09.009
  • Peer Reviewed
• [Journal Article] The mitochondrial protein PGAM5 suppresses energy consumption in brown adipocytes by repressing expression of uncoupling protein 1. (2020)
  • Author(s): Sugawara, S., Kanamaru, Y., Sekine, S., Maekawa, L., Takahashi, A., Yamamoto, T., Watanabe, K., Fujisawa, T., Hattori, K. and Ichijo, H.
  • Journal Title: J. Biol. Chem. Volume: 295 Issue: 17 Pages: 5588-5601
  • DOI: 10.1074/jbc.ra119.011508
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide siRNA screening reveals that DCAF4-mediated ubiquitination of optineurin stimulates autophagic degradation of Cu/Zn superoxide dismutase. (2020)
  • Author(s): Homma, K., Takahashi, H., Tsuburaya, N., Naguro, I., Fujisawa, T. and Ichijo, H.
  • Journal Title: J. Biol. Chem. Volume: 295 Issue: 10 Pages: 3148-3158
  • DOI: 10.1074/jbc.ra119.010239
  • Peer Reviewed / Open Access
• [Journal Article] Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains (2019)
  • Author(s): Lambert JP, Picaud S, Fujisawa T, Hou H, Savitsky P, Uuskula-Reimand L, Gupta GD, Abdouni H, Lin ZY, Tucholska M, Knight JDR, Gonzalez-Badillo B, St-Denis N, Newman JA, Stucki M, Pelletier L, Bandeira N, Wilson MD, Filippakopoulos P, Gingras AC
  • Journal Title: Molecular Cell Volume: 73 Issue: 3 Pages: 1-18
  • DOI: 10.1016/j.molcel.2018.11.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A small-molecule inhibitor of SOD1-Derlin-1 interaction ameliorates pathology in an ALS mouse model (2018)
  • Author(s): Tsuburaya, N., Homma, K., Higuchi, T., Balia, A., Yamakoshi, H., Shibata, N., Nakamura, S., Nakagawa, H., Ikeda, S., Umezawa, N., Kato, N., Yokoshima, S., Shibuya, M., Shimonishi, M., Kojima, H., Okabe, T., Nagano, T., Naguro, I., Imamura, K., Inoue, H., Fujisawa, T., and Ichijo, H.
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 2668-2668
  • DOI: 10.1038/s41467-018-05127-2
  • NAID: 120006546002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 亜鉛欠乏依存的なヒストンH3K14ac減弱メカニズムの解析 (2021)
  • Author(s): 藤澤貴央, 一條秀憲
  • Organizer: 第94回日本生化学会大会
• [Presentation] 亜鉛欠乏下における H3K14ac 認識タンパク質の機能解析 (2021)
  • Author(s): 竹中哲, 藤澤貴央, 一條秀憲
  • Organizer: 第94回日本生化学会大会
• [Presentation] 亜鉛欠乏刺激下におけるSOD1の新規結合因子からALSの病態分子機構に迫る (2021)
  • Author(s): 田中志和, 藤澤貴央, 一條秀憲
  • Organizer: 第94回日本生化学会大会
• [Presentation] 亜鉛欠乏依存的なヒストンH3K14ac減弱メカニズムの解析 (2021)
  • Author(s): 藤澤貴央, 一條秀憲
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] 亜鉛欠乏刺激下におけるSOD1の新規結合因子からALSの病態分子機構に迫る (2021)
  • Author(s): 田中志和, 藤澤貴央, 一條秀憲
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] MEK-ERK経路は亜鉛欠乏ストレス依存的なSOD1の構造変化を制御する (2020)
  • Author(s): 藤澤貴央, 竹中哲, 坪田充司, 一條秀憲
  • Organizer: 第93回日本生化学会大会
• [Presentation] 栄養飢餓状態におけるMBD3の発現量低下とその生理的意義の解析 (2020)
  • Author(s): 若月大晃, 藤澤貴央, 一條秀憲
  • Organizer: 第93回日本生化学会大会
• [Presentation] MEK-ERK経路は亜鉛欠乏ストレス依存的なSOD1の構造変化を制御する (2020)
  • Author(s): 竹中哲, 藤澤貴央, 坪田充司, 一條秀憲
  • Organizer: 第43回日本分子生物学会
• [Presentation] Analysis of Quality Control Autophagy of Aberrant ER Membrane Proteins Using a Novel Model Substrate (2019)
  • Author(s): Hayashi, Y., Fujisawa,T., Ichijo, H.
  • Organizer: Gordon Research Conference -Stress Proteins in Growth, Development and Disease-
  • Int'l Joint Research
• [Presentation] Molecular mechanism of zinc deficiency-induced structural change of SOD1 explored by a genome-wide siRNA screen (2019)
  • Author(s): Tsubota, A., Fujisawa, T., Ichijo, H.
  • Organizer: ISZB2019
  • Int'l Joint Research
• [Presentation] 新規モデル基質を用いた小胞体における不良膜タンパク質のオートファジー分解機構の解析 (2019)
  • Author(s): 林裕輝, 藤澤貴央, 一條秀憲
  • Organizer: 第92回日本生化学会大会
• [Presentation] ゲノムワイドsiRNAスクリーニングによる亜鉛欠乏依存的なSOD1構造変化制御機構の解明 (2019)
  • Author(s): 坪田充司, 藤澤貴央, 一條秀憲
  • Organizer: 第92回日本生化学会大会
• [Presentation] 筋萎縮性側索硬化症で見られるSOD1遺伝子変異の毒性発揮機構の解析 (2019)
  • Author(s): 田淵璃子, 藤澤貴央, 一條秀憲
  • Organizer: 第92回日本生化学会大会
• [Presentation] 小胞体における膜タンパク質の品質管理機構としての選択的オートファジー (2019)
  • Author(s): 林裕輝, 藤澤貴央, 一條秀憲
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] 筋萎縮性側索硬化症を引き起こすSOD1遺伝子変異に共通する構造変化 (2019)
  • Author(s): 田淵璃子, 藤澤貴央, 一條秀憲
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] 亜鉛欠乏依存的に構造変化したSOD1の機能解析 (2019)
  • Author(s): 前川リラ, 竹中哲, 坪田充司, 藤澤貴央, 一條秀憲
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] SOD1-Derlin-1結合を標的とした低分子化合物によるALS病態モデルの改善 (2018)
  • Author(s): 藤澤貴央、圓谷奈保美、本間謙吾、一條秀憲
  • Organizer: 第91回日本生化学会大会