Furukawa, Yoshiaki

写真a

Affiliation

Faculty of Science and Technology, Department of Chemistry (Yagami)

Position

Professor

Related Websites

External Links
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Career 【 Display / hide 】

  • 2001.04
    -
    2002.03

    京都大学大学院, 工学研究科分子工学専攻, 日本学術振興会 特別研究員 (DC2)

  • 2002.04
    -
    2003.03

    Northwestern University, Department of Chemistry, 日本学術振興会 特別研究員 (PD)

  • 2003.04
    -
    2005.03

    Northwestern University, Department of Chemistry, 日本学術振興会 海外特別研究員

  • 2005.04
    -
    2005.05

    Northwestern University, Department of Chemistry, Postdoctoral Researcher

  • 2005.06
    -
    2007.03

    RIKEN, 脳科学総合研究センター 構造神経病理研究チーム, 研究員

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Academic Background 【 Display / hide 】

  • 1993.04
    -
    1997.03

    Kyoto University, Faculty of Engineering, School of Industrial Chemistry

  • 1997.04
    -
    1999.03

    京都大学大学院, 工学研究科, 分子工学専攻修士課程

  • 1999.04
    -
    2002.03

    京都大学大学院, 工学研究科, 分子工学専攻博士後期課程

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Research Areas 【 Display / hide 】

  • Life Science / Functional biochemistry

  • Life Science / Functional biochemistry

  • Life Science / Pharmaceutical analytical chemistry and physicochemistry

  • Life Science / Pathophysiologic neuroscience

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Research Keywords 【 Display / hide 】

  • SOD1

  • 必須微量元素

  • 生体内亜鉛イオン

  • 生体内銅イオン

  • Neurodegenerative disease

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Papers 【 Display / hide 】

  • Cysteine residues in Cu,Zn-superoxide dismutase are essential to toxicity in Caenorhabditis elegans model of amyotrophic lateral sclerosis

    Ogawa, Mariko, Shidara, Hisashi, Oka, Kotaro, Kurosawa, Masaru, Nukina, Nobuyuki, Furukawa, Yoshiaki

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 463 ( 4 ) 1196 - 1202 2015.08

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  0006-291X

  • Conformational Disorder of the Most Immature Cu, Zn-Superoxide Dismutase Leading to Amyotrophic Lateral Sclerosis

    Furukawa, Yoshiaki, Anzai, Itsuki, Akiyama, Shuji, Imai, Mizue, Cruz, Fatima Joy C., Saio, Tomohide, Nagasawa, Kenichi, Nomura, Takao, Ishimori, Koichiro

    JOURNAL OF BIOLOGICAL CHEMISTRY 291 ( 8 ) 4144 - 4155 2016.02

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  0021-9258

  • A molecular mechanism realizing sequence-specific recognition of nucleic acids by TDP-43

    Furukawa, Yoshiaki, Suzuki, Yoh, Fukuoka, Mami, Nagasawa, Kenichi, Nakagome, Kenta, Shimizu, Hideaki, Mukaiyama, Atsushi, Akiyama, Shuji

    SCIENTIFIC REPORTS 6   4144 - 4155 2016.02

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  2045-2322

  • Cu/Zn-superoxide dismutase naturally fused with a β-propeller lactonase in Deinococcus radiodurans.

    Yoshiaki Furukawa, Masamichi Megata, Atsuko Shintani, Kaori Sue, Tomohiro Morohoshi, Masato Akutsu, Norifumi Muraki

    The Journal of biological chemistry 301 ( 8 ) 110499 - 110499 2025.08

    ISSN  00219258

    　View Summary

    Cu/Zn-superoxide dismutase (Cu/Zn-SOD) is an antioxidant enzyme widely present across species; however, the structural diversity and physiological roles of Cu/Zn-SOD are yet to be fully uncovered. Here, we show a unique type of Cu/Zn-SOD from Deinococcus radiodurans (DrSOD) with an additional β-propeller domain. Our structural analysis on DrSOD revealed a typical bacterial Cu/Zn-SOD domain, binding both a copper and zinc ion, alongside a six-bladed β-propeller domain coordinating a calcium ion. DrSOD was indeed expressed in D. radiodurans, but its deletion did not lead to any noticeable changes in resistance to DNA-damaging stresses, a characteristic trait of D. radiodurans. Despite this, the Cu/Zn-SOD domain retained superoxide dismutase activity, and the β-propeller domain was found to exhibit a lactonase activity specifically for hydrolyzing 2-coumaranone. Taken together, while the precise physiological role of DrSOD needs to be further investigated, our findings here reveal a unique multi-functional enzyme architecture, expanding the known structural diversity of Cu/Zn-SODs.

  • Metal-Responsive Up-Regulation of Bifunctional Disulfides for Suppressing Protein Misfolding and Promoting Oxidative Folding.

    Keita Mori, Tsubura Kuramochi, Motonori Matsusaki, Yuki Hashiguchi, Masaki Okumura, Tomohide Saio, Yoshiaki Furukawa, Kenta Arai, Takahiro Muraoka

    Angewandte Chemie (International ed. in English)    e202502187 2025

    ISSN  14337851

    　View Summary

    The stress-responsive up-regulation process is a sophisticated biological response to maintain cellular homeostasis. In intracellular anti-oxidant systems, the expression level of oxidoreductases is up-regulated under oxidative stress, mitigating oxidative damage on biomolecules and enhancing protein folding capacity. Herein, inspired by the biological system, we developed a synthetic folding promotor whose reactivity is up-regulated under stress conditions. We conjugated two metal-binding 1,4,7,11-tetraazacyclotetradecane (cyclam) ligands and a redox-active disulfide to obtain cyclam-SS, whose reactivity can be enhanced under metal-induced stress. Metal coordination increased the redox potential of cyclam-SS, activating it as an oxidant. While CuII ions severely hampered the oxidative folding of substrate polypeptides, cyclam-SS exhibited bifunctional folding-promoting properties, i) suppressing CuII-mediated misfolding and aggregation, and ii) harnessing CuII to enhance oxidative folding. Cyclam-SS was also useful for disulfide-bond formation to promote oxidative folding of pharmaceutical and pathological proteins, as demonstrated with proinsulin and superoxide dismutase 1 (SOD1). Furthermore, cyclam-SS protected cultured cells from copper-induced stress. Thus, we demonstrated the induction of the stress-responsive up-regulation process by a bifunctional folding promotor controlling the folding status of biologically important proteins under metal-induced stress. The strategy of "stress-responsive up-regulation" could aid the development of novel synthetic materials for treating intracellular stress and related disorders.

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Papers, etc., Registered in KOARA 【 Display / hide 】

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Reviews, Commentaries, etc. 【 Display / hide 】

  • システイン残基の酸化に伴うSOD1のミスフォールディングと筋萎縮性側索硬化症

    吉田萌乃, 明石知子, 田尻道子, 村木則文, 古川良明

    Fundamental Toxicological Sciences (Web) 10 ( Supplement )  2023

    ISSN  2189-115X

  • 神経変性疾患に見られる酸化的環境下でのSOD1タンパク質の構造異常化メカニズム

    吉田萌乃, 村木則文, 秋山修志, 古川良明

    日本蛋白質科学会年会プログラム・要旨集 23rd (CD-ROM) 2023

  • 変性性脊髄症における変異型SOD1の凝集メカニズム

    篠宥毅, 小畠結, 神志那弘明, 加藤龍一, 村木則文, 古川良明

    Fundamental Toxicological Sciences (Web) 10 ( Supplement )  2023

    ISSN  2189-115X

  • フラグメント抗体を利用した変性性脊髄症関連タンパク質SOD1の構造解析

    篠宥毅, 小畠結, 神志那弘明, 村木則文, 古川良明

    日本蛋白質科学会年会プログラム・要旨集 23rd (CD-ROM) 2023

  • Disruption of glymphatic system and slow in waste clearance in the SOD1-G93A mouse model of ALS

    Mikako Hirose, Asano Mito, Matsumoto Saori, Yamanaka Koji, Abe Yoichiro, Yasui Masato, Tokuda Eiichi, Furukawa Yoshiaki, Misawa Hidemi

    Proceedings for Annual Meeting of The Japanese Pharmacological Society (Japanese Pharmacological Society)  94   2-O-B3-1 2021

    　View Summary

    Amyotrophic lateral sclerosis (ALS) is a motor neuron specific neurodegenerative disease. Accumulation of mutant Cu/Zn-superoxide dismutase (SOD1) protein aggregate in the spinal motor neurons is a common pathological hallmark in several types of ALS animal models and patients. The glymphatic system is a waste clearance system in the central nervous system: the cerebrospinal fluid (CSF) flow through the perivascular space into interstitial spaces and the perivascular localization of aquaporin-4 (AQP4) promote its directional flow and waste clearance. We aimed to show involvement of glymphatic system in disease progression of ALS. We found AQP4 deficiency in SOD1-ALS mice accelerated disease onset and shortened survival period. In addition, abnormal SOD1 protein deposition was increased in SOD1-ALS/AQP4 knockout mice and the clearance of the protein from the spinal cord was slowed in AQP4 knockout mice. Furthermore, we observed AQP4 overexpression and mislocalization and detected glymphatic disfunction in ALS model mice for the first time. We suggest that the aberrant AQP4 distribution in the ALS model mice disrupts directional CSF flow and accelerates accumulation of abnormal proteins in the spinal cord. Our study would provide a new insight on improving the glymphatic system in ALS treatment strategies.

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Presentations 【 Display / hide 】

  • 神経変性疾患の病態形成に関わるタンパク質の構造変化

    古川良明

    分子研レターズ, 

    2016.09

  • Clinical and neuropathological study of an autopsied case of familial ALS with SOD1 mutation with very long survival

    Yo-ichi Takei, Kenya Oguchi, Takaaki Miyahira, Akiyo Hineo, Akinori Nakamura, Shinji Ohara, and Yoshiaki Furukawa

    The 68th Annual Meeting of the American Academy of Neurology (Vancouver, Canada) , 

    2016.04
    , 

    Poster presentation

  • 銅・亜鉛スーパーオキサイドディスムターゼの金属イオン結合状態を識別できる新規抗体の開発と筋萎縮性側索硬化症の病理解明への応用

    徳田　栄一、森崎　祐太、三澤　日出巳、渡邊　征爾、山中　宏二、古川　良明

    日本薬学会第136年会 (神奈川県・横浜市) , 

    2016.03
    , 

    Oral presentation (general)

  • タンパク質の熱変性を通じて理解する神経変性疾患の発症メカニズム

    安齋　樹、向山　厚、秋山　修志、古川　良明

    日本化学会第96春季年会 (京都府・京田辺市) , 

    2016.03
    , 

    Oral presentation (general)

  • 細胞内銅イオン輸送を可能にする銅シャペロンのドメイン構造

    福岡　真実、長野　功、古川　良明

    日本化学会第96春季年会 (京都府・京田辺市) , 

    2016.03
    , 

    Oral presentation (general)

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

  • 超硫黄化による銅シャペロン保護メカニズムの解明

    2024.04
    -
    2026.03

    学術変革領域研究(A), Principal investigator

  • 神経変性疾患の早期診断を指向した構造異常型タンパク質の極微量検出

    2022.06
    -
    2025.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 挑戦的研究（萌芽）, Principal investigator

  • 加齢に伴うタンパク質の構造・機能変化とその病理学的役割の解明

    2022.04
    -
    2026.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 基盤研究(B), Principal investigator

  • Detection of misfolded Cu/Zn-superoxide dismutase proteins with Caenorhabditis elegans

    2020.07
    -
    2022.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Furukawa Yoshiaki, Grant-in-Aid for Challenging Research (Exploratory), Principal investigator

    　View Summary

    Misfolding of mutant Cu/Zn-superoxide dismutase (SOD1) proteins is a pathological hallmark of a neurodegenerative disease, familial amyotrophic lateral sclerosis (fALS). Here, we describe a unique method to detect misfolded SOD1 by using a nematode, Caenorhabditis elegans. A mutant SOD1 protein is known to misfold into either amyloid-like, insoluble aggregates or disulfide-crosslinked, soluble oligomers in vitro. When those misfolded SOD1 proteins in vitro were administered to the worms, we observed adverse effects of the oligomers but not the aggregates on C. elegans such as shortened lifespan, decreased motility, and deteriorated defecation. While a mechanism behind the trapping of worms with the oligomers remains obscure, this study reveals that C. elegans has potential to detect misfolded proteins even in a sub-micromolar concentration.

  • 生命金属動態を制御するシャペロン分子ネットワークの解明

    2019.06
    -
    2024.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research on Innovative Areas, Principal investigator

    　View Summary

    本研究では、銅・亜鉛スーパーオキシドディスムターゼ（SOD1, SodC）の成熟化過程に着目し、生体内における生命金属動態制御の理解と、その破綻がもたらす疾患発症機序の解明を目標としている。その実現に向けて本年度は、バクテリアSodCによる銅イオン獲得のメカニズムとヒトSOD1への銅・亜鉛イオンの結合メカニズムの解明に取り組んだ。まず、SodCによる銅イオン獲得のメカニズムについては、SOD1/SodCに保存された分子内ジスルフィド結合に関わるシステイン残基が、銅イオンや亜鉛イオンの獲得に重要な役割を果たしうることを明らかにできた。また、ヒトSOD1への銅・亜鉛イオン結合プロセスにおいては、分子内ジスルフィド結合が形成していると、銅・亜鉛イオンの結合サイトに金属イオンがランダムに結合してしまうことがわかった。特に、銅イオン結合サイトへの亜鉛イオンの結合を防ぐためには、ジスルフィド結合が切断されている必要があった。以上より、SOD1やSodCへの金属イオン結合は、ジスルフィド結合に形成するシステイン残基によって制御されていることがわかった。これらの成果は、２報の原著論文として報告するとともに、６件の招待講演として発表を行った。

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Awards 【 Display / hide 】

  • 平成２８年秀でた利用成果

    古川 良明, 2016, 文部科学省「ナノテクノロジープラットフォーム」, 神経変性疾患の発症に関わるタンパク質ミスフォールディング

  • 若手奨励賞

    古川 良明, 2009, 日本生物物理学会, ポリグルタミン病の新たな分子病理メカニズム－タンパク質線維の構造伝播による発症制御の可能性

  • 若手招待講演者

    古川 良明, 2005, 日本生物物理学会, 筋萎縮性側索硬化症に見られるSOD1蛋白質の凝集化機構－翻訳後修飾による構造制御の重要性－

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Courses Taught 【 Display / hide 】

  • TOPICS IN BIOINORGANIC CHEMISTRY

    2025

  • SEMINAR IN CHEMISTRY

    2025

  • MOLECULAR BIOLOGY (BIOLOGICAL CHEMISTRY 3)

    2025

  • LABORATORY IN SCIENCE

    2025

  • LABORATORIES IN CHEMISTRY 1

    2025

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Memberships in Academic Societies 【 Display / hide 】

  • The Society of Biological Inorganic Chemistry, 

    2013.03
    -
    Present

  • 日本蛋白質科学会, 

    2010.03
    -
    Present

  • The Society for Neuroscience, 

    2009.03
    -
    Present

  • 日本神経科学学会, 

    2008.04
    -
    Present

  • 日本生物物理学会, 

    1998.03
    -
    Present

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Committee Experiences 【 Display / hide 】

  • 2024.07
    -
    Present

    評議員, 金属の関与する生体関連反応シンポジウム

  • 2024.06
    -
    Present

    副会長, 生命金属科学研究会

  • 2024.03
    -
    Present

    委員, 日本学術振興会R051メタロミクス委員会

  • 2022
    -
    2023

    代議員, 日本化学会関東支部

  • 2019
    -
    Present

    幹事, 日本毒性学会 生体金属部会

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