異常構造型脳タンパク質の経口摂取による神経変性疾患発症の可能性

• Project Area: Prevention of brain protein aging and dementia
• Project/Area Number: 17H05705
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Keio University
• Principal Investigator: 古川 良明 慶應義塾大学, 理工学部(矢上), 准教授 (40415287)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 金属タンパク質 / 蛋白質 / 神経変性疾患 / 銅タンパク質

Outline of Annual Research Achievements

酸化ストレスの増大は、タンパク質などの生体分子に酸化的な修飾を施すことが知られており、様々な疾患で観察される。例えば、神経変性疾患の一種である筋萎縮性側索硬化症（ALS）では、各種の酸化ストレスマーカーが病変部位である脊髄において増大するとともに、銅・亜鉛スーパーオキシドディスムターゼ（SOD1）の構造異常化（ミスフォールディング）が進行するとされている。実際、精製したSOD1に高濃度（mM）の過酸化水素（H2O2）を添加することでTrp/His/Cysが酸化されることから、酸化修飾によるSOD1のミスフォールディング機構が提案されている。しかし、生体内でのH2O2濃度がmMレベルにまで高くなることがあるのかは甚だ疑問であり、酸化ストレスの増大がSOD1の構造にもたらす影響は明らかとなっていない。そこで、低濃度（microM）のH2O2がSOD1の構造にもたらす影響を検討したところ、タンパク質表面に露出したCys111のチオール基がスルフェニル化されることが確認された。天然状態のSOD1はホモ二量体として存在しているが、スルフェニル化を通じて異常化したSOD1は単量体となり、構造揺らぎが増大したミスフォールド体となっていることも分かった。つまり、生体内で生じるH2O2によって、SOD1はスルフェニル化されうることが十分に考えられ、金属イオンがさらに解離することでミスフォールドすることが考えられた

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Sequence- and seed-structure-dependent polymorphic fibrils of alpha-synuclein (2019)
  • Author(s): Tanaka Goki、Yamanaka Tomoyuki、Furukawa Yoshiaki、Kajimura Naoko、Mitsuoka Kaoru、Nukina Nobuyuki
  • Journal Title: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease Volume: 19 Issue: 6 Pages: 30065-1
  • DOI: 10.1016/j.bbadis.2019.02.013
  • Peer Reviewed
• [Journal Article] Biochemical and morphological classification of disease-associated alpha-synuclein mutants aggregates (2019)
  • Author(s): Tanaka Goki、Yamanaka Tomoyuki、Furukawa Yoshiaki、Kajimura Naoko、Mitsuoka Kaoru、Nukina Nobuyuki
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 508 Issue: 3 Pages: 729-734
  • DOI: 10.1016/j.bbrc.2018.11.200
  • Peer Reviewed
• [Journal Article] Pathological roles of copper dynamics in amyotrophic lateral sclerosis (2018)
  • Author(s): 古川良明
  • Journal Title: 生化学 Volume: 90 Issue: 3 Pages: 311-319
  • DOI: 10.14952/SEIKAGAKU.2018.900311
  • ISSN: 0037-1017
  • Year and Date: 2018-06-25
• [Journal Article] Rapid dissemination of alpha-synuclein seeds through neural circuits in an in-vivo prion-like seeding experiment (2018)
  • Author(s): Okuzumi Ayami、Kurosawa Masaru、Hatano Taku、Takanashi Masashi、Nojiri Shuuko、Fukuhara Takeshi、Yamanaka Tomoyuki、Miyazaki Haruko、Yoshinaga Saki、Furukawa Yoshiaki、Shimogori Tomomi、Hattori Nobutaka、Nukina Nobuyuki
  • Journal Title: Acta Neuropathologica Communications Volume: 6 Issue: 1 Pages: 96-96
  • DOI: 10.1186/s40478-018-0587-0
  • Peer Reviewed / Open Access
• [Journal Article] Elimination of TDP-43 inclusions linked to amyotrophic lateral sclerosis by a misfolding-specific intrabody with dual proteolytic signals. (2018)
  • Author(s): Tamaki Y, Shodai A, Morimura T, Hikiami R, Minamiyama S, Ayaki T, Tooyama I, Furukawa Y, Takahashi R, Urushitani M.
  • Journal Title: Scientific Reports Volume: 印刷中 Issue: 1 Pages: 6030-6030
  • DOI: 10.1038/s41598-018-24463-3
  • NAID: 120006482849
  • Peer Reviewed / Open Access
• [Journal Article] Cu/Zn-superoxide dismutase forms fibrillar hydrogels in a pH-dependent manner via a water-rich extended intermediate state (2018)
  • Author(s): Fujiwara Noriko、Wagatsuma Michiru、Oba Naoto、Yoshihara Daisaku、Tokuda Eiichi、Sakiyama Haruhiko、Eguchi Hironobu、Ichihashi Motoko、Furukawa Yoshiaki、Inoue Tadashi、Suzuki Keiichiro
  • Journal Title: PLOS ONE Volume: 13 Issue: 10 Pages: e0205090-e0205090
  • DOI: 10.1371/journal.pone.0205090
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a novel zinc-binding protein, C1orf123, as an interactor with a heavy metal-associated domain (2018)
  • Author(s): Furukawa Yoshiaki、Lim Carolyn、Tosha Takehiko、Yoshida Koki、Hagai Tomoaki、Akiyama Shuji、Watanabe Shoji、Nakagome Kenta、Shiro Yoshitsugu
  • Journal Title: PLOS ONE Volume: 13 Issue: 9 Pages: e0204355-e0204355
  • DOI: 10.1371/journal.pone.0204355
  • Peer Reviewed / Open Access
• [Journal Article] A copper-deficient form of mutant cu/Zn-superoxide dismutase as an early pathological species in amyotrophic lateral sclerosis (2018)
  • Author(s): Tokuda Eiichi、Nomura Takao、Ohara Shinji、Watanabe Seiji、Yamanaka Koji、Morisaki Yuta、Misawa Hidemi、Furukawa Yoshiaki
  • Journal Title: Biochimica et Biophysica Acta - Molecular Basis of Disease Volume: 印刷中 Issue: 6 Pages: 2119-2130
  • DOI: 10.1016/j.bbadis.2018.03.015
  • Peer Reviewed / Open Access
• [Journal Article] An essential role of N-terminal domain of copper chaperone in the enzymatic activation of Cu/Zn-superoxide dismutase (2017)
  • Author(s): Fukuoka Mami、Tokuda Eiichi、Nakagome Kenta、Wu Zhiliang、Nagano Isao、Furukawa Yoshiaki
  • Journal Title: Journal of Inorganic Biochemistry Volume: 175 Pages: 208-216
  • DOI: 10.1016/j.jinorgbio.2017.07.036
  • Peer Reviewed
• [Journal Article] Abnormal protein oligomers for neurodegeneration (2017)
  • Author(s): Tokuda Eiichi、Furukawa Yoshiaki
  • Journal Title: Oncotarget Volume: 8 Issue: 25 Pages: 39943-39944
  • DOI: 10.18632/oncotarget.18030
  • Peer Reviewed
• [Journal Article] Aggregation of FET Proteins as a Pathological Change in Amyotrophic Lateral Sclerosis (2017)
  • Author(s): Furukawa Yoshiaki、Tokuda Eiichi
  • Journal Title: Advances in Experimental Medicine and Biology Volume: 925 Pages: 1-12
  • DOI: 10.1007/5584_2016_32
  • ISBN: 9789811037092, 9789811037108
  • Peer Reviewed
• [Presentation] Metal-deficiency in Cu/Zn-superoxide dismutase: a potential cause of motor neuron disease, ALS (2018)
  • Author(s): Yoshiaki Furukawa
  • Organizer: 9th Asian Biological Inorganic Chemistry Conference
  • Int'l Joint Research / Invited
• [Presentation] A misfolding mechanism of Cu/Zn-superoxide dismutase under oxidative conditions of amyotrophic lateral sclerosis (2018)
  • Author(s): Itsuki Anzai, Eiichi Tokuda, Atsushi Mukaiyama, Shuji Akiyama, and Yoshiaki Furukawa
  • Organizer: 9th Asian Biological Inorganic Chemistry Conference
  • Int'l Joint Research
• [Presentation] Factors controlling expression levels of periplasmic Cu/Zn-superoxide dismutase in Escherichia coli (2018)
  • Author(s): Koki Yoshida and Yoshiaki Furukawa
  • Organizer: 9th Asian Biological Inorganic Chemistry Conference
  • Int'l Joint Research
• [Presentation] Conformation-dependent toxicity of Cu/Zn-superoxide dismutase in Caenorhabditis elegans (2018)
  • Author(s): Ayano Toba, Eiichi Tokuda, and Yoshiaki Furukawa
  • Organizer: 9th Asian Biological Inorganic Chemistry Conference
  • Int'l Joint Research
• [Presentation] A network for intracellular copper distribution controlled by interactions between copper chaperones (2018)
  • Author(s): Kyoka Matsumoto, Kenta Nakagome, and Yoshiaki Furukawa
  • Organizer: 9th Asian Biological Inorganic Chemistry Conference
  • Int'l Joint Research
• [Presentation] Wild-type SOD1 is misfolded in cerebrospinal fluid of sporadic ALS (2018)
  • Author(s): Yoshiaki Furukawa, Eiichi Tokuda, Shinji Ohara, Noriko Fujiwara
  • Organizer: 22nd International Symposium on ALS/MND
  • Int'l Joint Research
• [Presentation] 神経変性疾患に見られる生体内銅イオン動態の異常 (2018)
  • Author(s): 古川良明
  • Organizer: 第６回メタロミクス研究フォーラム
  • Invited
• [Presentation] A mechanism on copper acquisition of bacterial Cu/Zn-superoxide dismutase (2018)
  • Author(s): 古川良明
  • Organizer: 第５６回日本生物物理学会年会
• [Presentation] 筋萎縮性側索硬化症における銅・亜鉛結合タンパク質SOD1のミスフォールディングメカニズム (2018)
  • Author(s): 古川良明
  • Organizer: 第１８回日本蛋白質科学会年会
• [Presentation] 筋萎縮性側索硬化症に見られる銅・亜鉛結合タンパク質SOD1のミスフォールディングメカニズム (2017)
  • Author(s): 古川良明
  • Organizer: 第5回メタロミクス研究フォーラム
  • Invited
• [Presentation] 生体内の銅イオン動態と神経変性疾患 (2017)
  • Author(s): 古川良明
  • Organizer: 分子研研究会「生体金属動態」
  • Invited
• [Presentation] Roles of metallochaperone in the activation of Cu/Zn-superoxide dismutase (2017)
  • Author(s): 古川良明
  • Organizer: 第17回日本蛋白質科学会年会
  • Invited
• [Presentation] SOD1-linked familial ALS with marked intrafamilial phenotypic variation. How clinical features relate to pathology? (2017)
  • Author(s): Shinji Ohara, Yo-ichi Takei, Akinori Nakamura, Kenya Oguchi, Hidemi Misawa, and Yoshiaki Furukawa
  • Organizer: International Conference on Neurology and Brain Disorders
  • Int'l Joint Research / Invited
• [Presentation] Development of peptides that specifically recognize misfolded SOD1 proteins in amyotrophic lateral sclerosis (2017)
  • Author(s): Eiichi Tokuda, Kenichi Nagasawa, Takao Nomura, Hidemi Misawa, Shinji Ohara, Koji Yamanaka, and Yoshiaki Furukawa
  • Organizer: 28th International Symposium on ALS/MND
  • Int'l Joint Research
• [Presentation] 筋萎縮性側索硬化症にみられる変異型SOD1への金属イオン結合の異常 (2017)
  • Author(s): 古川良明、徳田栄一、大原慎司、山中宏二、三澤日出巳
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] A mechanism of enzymatic activation of Cu/Zn-superoxide dismutase by its copper chaperone (2017)
  • Author(s): Yoshiaki Furukawa and Mami Fukuoka
  • Organizer: 日本生物物理学会第55回年会
• [Presentation] Development of peptides that specifically recognize misfolded SOD1 proteins in amyotrophic lateral sclerosis (2017)
  • Author(s): 徳田栄一、長澤健一、野村尚生、三澤日出巳、山中宏二、古川良明
  • Organizer: 第40回日本神経科学会大会
• [Presentation] タンパク質の構造異常を検出できるファージの開発と神経変性疾患の病理解明への応用 (2017)
  • Author(s): 古川良明、徳田栄一、長澤健一、野村尚生、山中宏二、三澤日出巳、大原慎司
  • Organizer: 第44回生体分子科学討論会
• [Book] 食と医療 2018 FALL－WINTER Vol．7 (2018)
  • Author(s): 「食と医療」事務局
  • Total Pages: 116
  • Publisher: 講談社
  • ISBN: 9784065140581
• [Remarks] 慶應理工のタンパク質科学（生命機構化学・古川研究室）
  • URL: https://furukawa.mixh.jp
• [Remarks] Furukawa Lab. Home
  • URL: http://www.chem.keio.ac.jp/~furukawa/index.html