Molecular mechanism of zinc-induced neurotoxicity : involvement of Ca and ER stress

• Project/Area Number: 21590145
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Environmental pharmacy
• Research Institution: Kyushu University of Health and Welfare
• Principal Investigator: KAWAHARA Masahiro 九州保健福祉大学, 薬学部, 教授 (40224828)
• Co-Investigator(Kenkyū-buntansha): SADAKANE Yutaka 鈴鹿医療科学大学, 薬学部, 教授 (60293304) ; KOYAMA Hironari 九州保健福祉大学, 薬学部, 助手 (70567718)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2010: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2009: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 中毒学 / 無機金属毒性 / 亜鉛 / カルシウム / アポトーシス / カルノシン / プリオン / コンフォメーション / 銅 / 小胞体ストレス / アルツハイマー病 / プリオン病 / 脳血管性認知症 / イメージング

Research Abstract

Zinc(Zn) is neurotoxic and causes neurodegeneration following transient global ischemia and plays a crucial role in the pathogenesis of vascular-type dementia. We investigated the molecular mechanisms of Zn-induced neurotoxicity in vitro. The analysis of upregulated genes during Zn-induced neuronal death revealed that the significance of ER stress. These new results indicate that the disruption of Ca2+homeostasis and ER stress in the molecular mechanism of Zn-induced neurotoxicity, and are useful for the search for protective substances for vasucular dementia.

Research Products

• [Journal Article] Zinc neurotoxicity and the pathogenesis of vascular-type dementia : Involvement of calcium dyshomeostasis and carnosine (2012)
  • Author(s): Koyama H, Konoha K, Sadakane Y, Ohkawara S, and Kawahara M
  • Journal Title: J. Clin Toxicol Volume: (in press)
  • Peer Reviewed
• [Journal Article] 亜鉛と認知症:脳の中のヤヌス (2012)
  • Author(s): 川原正博
  • Journal Title: ファルマシア Volume: 48 Pages: 216-220
  • NAID: 110009901048
• [Journal Article] 神経疾患と微量金属 (2012)
  • Author(s): 川原正博、小山裕也、大河原晋
  • Journal Title: 金属 Volume: 82 Pages: 19-27
• [Journal Article] Zinc neurotoxicity and the pathogenesis of vascular-type dementia : Involvement of calcium dyshomeostasis and carnosine (2012)
  • Author(s): Koyama H, Konoha K, Sadakane Y, Ohkawara S, Kawahara M
  • Journal Title: J.Clin Toxicol. Volume: (In press)
  • Peer Reviewed
• [Journal Article] Membrane incorporation, channel formation, and disruption of calcium homeostasis by Alzheimer's s-amyloid protein (2011)
  • Author(s): Kawahara M., Ohtsuka I., Yokoyama S., Kato-Negishi M. and Sadakane Y
  • Journal Title: Int. J. Alzheimer Dis. Pages: 304583-304583
  • Peer Reviewed
• [Journal Article] Zinc, copper, and carnosine attenuate neurotoxicity of prion fragment PrP106-126 (2011)
  • Author(s): Kawahara M, Koyama H., Nagata T., Sadakane Y.
  • Journal Title: Metallomics Volume: 3 Pages: 726-734
  • Peer Reviewed
• [Journal Article] アミロイド形成蛋白の高次構造変化と神経毒性に及ぼす金属の影響 (2011)
  • Author(s): 川原正博、小山裕也、定金豊
  • Journal Title: Biomed. Res. Trace Elements Volume: 22 Pages: 7-14
  • NAID: 10028117958
  • Peer Reviewed
• [Journal Article] Link between aluminum and the pathogenesis of Alzheimer's disease : the integration of the aluminum and amyloid cascade hypotheses (2011)
  • Author(s): Kawahara M. and Kato-Negishi M.
  • Journal Title: Int. J. Alzheimer Dis. Pages: 276393-276393
  • Peer Reviewed
• [Journal Article] アミロイド形成蛋白の高次構造変化と神経毒性に及ぼす金属の影響 (2011)
  • Author(s): 川原正博、小山裕也、定金豊
  • Journal Title: Biomed.Res.Trace Elements Volume: 28 Pages: 49-53
  • NAID: 10028117958
  • Peer Reviewed
• [Journal Article] Membrane incorporation, channel formation, and disruption of calcium homeostasis by Alzheimer's β-amyloid protein (2011)
  • Author(s): Kawahara M., Ohtsuka I., Yokoyama S., Kato-Negishi M., Sadakane Y.
  • Journal Title: Int.J.Alzheimer Dis. Volume: 2011 Pages: 304583-304583
  • Peer Reviewed
• [Journal Article] Link between aluminum and the pathogenesis of Alzheimer's disease : the integration of the aluminum and amyloid cascade hypotheses (2011)
  • Author(s): Kawahara M., Kato-Negishi M.
  • Journal Title: Int.J.Alzheimer Dis. Volume: 2011 Pages: 276393-276393
  • Peer Reviewed
• [Journal Article] Role of calcium dyshomeostasis via amyloid channels in the pathogenesis of Alzheimer's disease (2010)
  • Author(s): Kawahara M
  • Journal Title: Current Pharmaceutical Design Volume: 16 Pages: 2779-2789
  • Peer Reviewed
• [Journal Article] Effects of UV-B irradiation on the stability of amino acids and peptides (2010)
  • Author(s): Sadakane Y, Fukuhara T, Kawahara M, Nakagomi K
  • Journal Title: J. KUHW Volume: 11 Pages: 147-152
  • NAID: 110007577967
  • Peer Reviewed
• [Journal Article] Quantification of structural alterations of L-Asp and L-Asn residues in peptides related to neuronal disease by reversed-phase HPLC (2010)
  • Author(s): Sadakane Y, Konoha K., Kawahara M., Nakagomi K.
  • Journal Title: Chem. & Biodivers Volume: 7 Pages: 1371-1379
  • Peer Reviewed
• [Journal Article] Ligand structure for photoaffinity labeling of carbohydrate-binding protein (2010)
  • Author(s): Sadakane Y, Otsuka I, Konoha K, Koyama H, Kawahara M, Hatanaka Y
  • Journal Title: Photomedicine and Photobiology Volume: 31 Pages: 9-10
  • Peer Reviewed
• [Journal Article] Quantification of structural alterations of L-Asp and L-Asn residues in peptides related to neuronal disease by reversed-phase HPLC (2010)
  • Author(s): Sadakane Y, Konoha K., Kawahara M., Nakagomi K.
  • Journal Title: Chem.& Biodivers Volume: 7 Pages: 1371-1379
  • Peer Reviewed
• [Journal Article] Effects of UV-B irradiation on the stability of amino acids and peptides. (2010)
  • Author(s): Sadakane Y, Fukuhara T, Kawahara M, Nakagomi K
  • Journal Title: J.KUHW Volume: 11 Pages: 147-152
  • NAID: 110007577967
• [Journal Article] Quantification of structural alterations of L-Asp and L-Asn residues in peptides related to neuronal disease by reversed-phase HPLC (2010)
  • Author(s): Sadakane Y, Konoha K., Kawahara M., Nakagomi K
  • Journal Title: Chem. & Biodivers (In press)
  • Peer Reviewed
• [Journal Article] Effects of UV-B irradiation on the stability of amino acids and peptides. (2010)
  • Author(s): Sadakane Y, Fukuhara T, Kawahara M, Nakagomi K
  • Journal Title: J.KUHW 11 Pages: 147-152
  • NAID: 110007577967
• [Journal Article] Ligand structure for photoaffinity labeling of carbohydrate-binding protein. (2010)
  • Author(s): Sadakane Y, Otsuka I, Konoha K, Koyama H, Kawahara M, Hatanaka Y
  • Journal Title: Photomedicine and Photobiology 31(In press)
• [Journal Article] Analysis of structural alternation of L-Asp and L-Asn residures in the peptides related to neuronal conformation disease (2010)
  • Author(s): Sadakane Y., Konoha K., Kawahara M
  • Journal Title: KURRI-KR 148 Pages: 1-5
• [Journal Article] Preparation of recombinant Asp-isomerized crystalline and analysis of the effects of Asp alternation on protein function and structure using radiation. (2010)
  • Author(s): Sadakane Y., Fujii N
  • Journal Title: KURRI Prog. Rep 2008 Pages: 6-5
• [Journal Article] (2010)
  • Author(s): Kawahara M
  • Journal Title: Metals and Neurodegeneration (Editor : Shile Huang)(Research Signpost) Pages: 15-56
• [Journal Article] (2010)
  • Author(s): Kawahara M, Konoha K, Nagata T, Sadakane Y
  • Journal Title: Frontiers in CNS Drug Discovery(Bentham Science Publishers) Pages: 21-30
• [Journal Article] Analysis of structural alternation of L-Asp and L-Asn residures in the peptides related to neuronal conformation disease (2009)
  • Author(s): Sadakane Y., Konoha K., Kawahara M.
  • Journal Title: KURRI-KR Volume: 148 Pages: 1-5
  • Peer Reviewed
• [Journal Article] Calcium dyshomeostasis and neurotoxicity of Alzheimer's beta-amyloid protein (2009)
  • Author(s): Kawahara M. Negishi-Kato M, Sadakane Y.
  • Journal Title: Expert Rev Neurother Volume: 9 Pages: 681-93
  • Peer Reviewed
• [Journal Article] Calcium dyshomeostasis and neurotoxicity of Alzheimer's beta-amyloid protein. (2009)
  • Author(s): Kawahara M., Negishi-Kato M, Sadakane Y
  • Journal Title: Expert Rev Neurother 9 Pages: 681-693
  • Peer Reviewed
• [Presentation] アルツハイマーβペプチドのN末側アミノ酸の構造的変化と線維化への影響 (2012)
  • Author(s): 定金豊,小山裕也,川原正博
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 札幌
• [Presentation] PrP106-126の高次構造変化に重要な配列 (2012)
  • Author(s): 小山裕也,坂口哲陛,大河原晋,定金豊,川原正博
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 札幌
• [Presentation] アルミニウムの神経毒性と神経疾患との関連 (2011)
  • Author(s): 川原正博、小山裕也
  • Organizer: 第22回日本微量元素学会シンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2011-07-02
• [Presentation] 創薬シーズとしてのカルノシン (2011)
  • Author(s): 川原正博
  • Organizer: 第4回薬学研究フォーラムin東京-九州からの情報発信による企業との共同研究マッチング-
  • Place of Presentation: 東京
  • Year and Date: 2011-01-23
• [Presentation] 創薬シーズとしてのカルノシン (2011)
  • Author(s): 川原正博
  • Organizer: 第4回薬学研究フォーラムin東京-九州からの情報発信による企業との共同研究マッチング-」日本薬学会九州支部・九州薬科学研究教育連合主催
  • Place of Presentation: 東京
  • Year and Date: 2011-01-02
• [Presentation] PrP断片ペプチドに対する亜鉛および銅の影響 (2011)
  • Author(s): 小山裕也,永田哲也,定金豊,川原正博
  • Organizer: 日本薬学会第131年会
  • Place of Presentation: 静岡
• [Presentation] コンフォメーション病に関与するペプチド中のアスanti-stressanti-oxidantanti-glycationanti-painanti-crosslink(Alzheimer, prion) pHbalanceCarnosineCH2CH2CNHOCHCCH2OHONNHH2Nパラギンおよびアスパラギン酸残基の構造変化と生理活性 (2011)
  • Author(s): 定金豊,小山裕也,川原正博
  • Organizer: 日本薬学会第131年会
  • Place of Presentation: 静岡
• [Presentation] Effects of trace elements on the conformational changes of amyloidogenic proteins and their neurotoxicity (2011)
  • Author(s): Kawahara M.
  • Organizer: 5th International Conference on Metals and Genetics
  • Place of Presentation: Kobe, Japan
• [Presentation] Zinc, copper, and carnosine attenuate neurotoxicity of prion fragment PrP106-126 (2011)
  • Author(s): Koyama H, Okahara M, Sakaguchi T, Sadakane Y and Kawahara M
  • Organizer: 5th International Conference on Metals and Genetics
  • Place of Presentation: Kobe, Japan
• [Presentation] Molecular Mechanism of zinc-induced neurotoxicity (2011)
  • Author(s): Kawahara M.
  • Organizer: ISTERH(International Society for Trace Element Research in Humans)
  • Place of Presentation: Antalya, Turkey
• [Presentation] Molecular Mechanism of zinc-induced neurotoxicity (2011)
  • Author(s): Kawahara M
  • Organizer: ISTERH (International Society for Trace Element Research in Humans)
  • Place of Presentation: Antalya, Turkey
• [Presentation] 認知症から脳を保護するカルノシン (2010)
  • Author(s): 川原正博
  • Organizer: 都市エリア産学官連携事業第9回浜辺のセミナー
  • Place of Presentation: 宮崎
  • Year and Date: 2010-10-25
• [Presentation] 認知症から脳を保護するカルノシン (2010)
  • Author(s): 川原正博
  • Organizer: 都市エリア産学官連携事業 第9回浜辺のセミナー
  • Place of Presentation: 宮崎
  • Year and Date: 2010-10-25
• [Presentation] プリオンペプチド断片(106-126)中のAsn残基の構造的変化と生理活性について (2010)
  • Author(s): 定金豊,小山裕也,大塚功,木葉敬子,川原正博
  • Organizer: 第6回D-アミノ酸研究会学術講演会
  • Place of Presentation: 富山
  • Year and Date: 2010-09-17
• [Presentation] カルノシンって何?-宮崎の食で認知症を防ぐ- (2010)
  • Author(s): 川原正博
  • Organizer: 都市エリア産学官連携事業第8回浜辺のセミナー
  • Place of Presentation: 延岡
  • Year and Date: 2010-08-30
• [Presentation] カルノシンって何?-宮崎の食で認知症を防ぐ (2010)
  • Author(s): 川原正博
  • Organizer: 都市エリア産学官連携事業 第8回浜辺のセミナー
  • Place of Presentation: 延岡
  • Year and Date: 2010-08-30
• [Presentation] 糖鎖機能の効率的化未明を目指した光反応性糖鎖リガンドの製作 (2010)
  • Author(s): 定金豊,大塚功,川原正博,畑中保丸
  • Organizer: 第32回日本光医学・光生物学会
  • Place of Presentation: 東京
  • Year and Date: 2010-07-30
• [Presentation] プリオンペプチド断片中のアスパラギン残基の構造的変化と生理活性 (2010)
  • Author(s): 定金豊
  • Organizer: 第130年会 日本薬学会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-30
• [Presentation] プリオン蛋白による培養細胞に対する亜鉛および銅の影響 (2010)
  • Author(s): 小山裕也
  • Organizer: 第130年会 日本薬学会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-30
• [Presentation] Carnosine誘導体合成とGT1-7系における神経細胞保護効果 (2010)
  • Author(s): 鳥や尾篤
  • Organizer: 第130年会 日本薬学会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-30
• [Presentation] 光アフィニティーラベル法による糖鎖機能解明を目指した新規分子ツールの創製 (2010)
  • Author(s): 大塚功
  • Organizer: 第130年会 日本薬学会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-29
• [Presentation] 微量金属の神経毒性と神経変性疾患 (2010)
  • Author(s): 川原正博
  • Organizer: 第130年会 日本薬学会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-28
• [Presentation] プリオン蛋白による培養細胞に対する亜鉛および銅の影響 (2010)
  • Author(s): 小山裕也,永田哲也,定金豊,大塚功,戸泉文江,横山祥子,川原正博
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
• [Presentation] carnosine誘導体合成とGT1-7系における神経細胞保護効果 (2010)
  • Author(s): 鳥や尾篤、宮越辰則、反田和宏,渡邉暁子、坂本正徳、木葉敬子、定金豊、川原正博、山崎哲郎
  • Organizer: 日本薬学会第130回年会
  • Place of Presentation: 岡山
• [Presentation] プリオンペプチド断片(106-126)中のアスパラギン残基の自発的構造変化と生理機能 (2010)
  • Author(s): 定金豊,小山裕也、大塚功、川原正博
  • Organizer: 第27回日本薬学会九州支部大会
  • Place of Presentation: 長崎
• [Presentation] PrP断片ペプチドの神経毒性に対する亜鉛および銅の影響 (2010)
  • Author(s): 小山裕也、永田哲也、定金豊、川原正博
  • Organizer: 第27回日本薬学会九州支部大会
  • Place of Presentation: 長崎
• [Presentation] Alterations of gene expressions during neuronal death after zinc exposure : implications of calcium dyshomeostasis (2010)
  • Author(s): Kawahara M., Koyama H., Sadakane Y.
  • Organizer: Society for Neuroscience
  • Place of Presentation: San Diego
• [Presentation] プリオン蛋白断片ペプチドのコンフォメーション変化と神経毒性に及ぼす微量金属の影響 (2010)
  • Author(s): 川原正博、小山裕也、定金豊
  • Organizer: 第2回メタロミクス研究フォーラム
  • Place of Presentation: 京都
• [Presentation] Effects of zinc and copper on conformational changes and neurotoxicity of prion fragment peptide(PrP106-126) (2010)
  • Author(s): 小山裕也、定金豊、大塚功、川原正博
  • Organizer: 第20回金属の関与する生体関連反応シンポジウム
  • Place of Presentation: 徳島
• [Presentation] Effects of zinc and copper on conformational changes and neurotoxicity of prion fragment peptide (PrP106-126) (2010)
  • Author(s): 小山裕也、定金豊、大塚功、川原正博
  • Organizer: 第20回金属の関与する生体関連反応シンポジウム(SRM2010)
  • Place of Presentation: 徳島
• [Presentation] 糖鎖結合タンパク質に適した光化学的スクリーニング法の開発 (2009)
  • Author(s): 定金豊,木葉敬子,川原正博,畑中保丸
  • Organizer: 第26回日本薬学会九州支部大会
  • Place of Presentation: 福岡
  • Year and Date: 2009-12-12
• [Presentation] 糖鎖結合タンパク質に適した光化学的スクリーニング法の開発 (2009)
  • Author(s): 定金豊
  • Organizer: 第26回 日本薬学会九州支部大会
  • Place of Presentation: 福岡
  • Year and Date: 2009-12-12
• [Presentation] 神経疾患に関わるペプチド中のアスパラギンおよびアスパラギン酸残基の構造的変化と生理活性 (2009)
  • Author(s): 定金豊
  • Organizer: 京都大学原子炉実験所・専門研究会「第2回タンパク質の異常凝集とその防御・修復機構に関する研究会」
  • Place of Presentation: 大阪
  • Year and Date: 2009-11-12
• [Presentation] 宮崎県産海産物から老年性認知症予防・治療薬を探索する (2009)
  • Author(s): 川原正博
  • Organizer: 第3回薬学研究フォーラムin東京-九州からの情報発信-
  • Place of Presentation: 東京
  • Year and Date: 2009-11-03
• [Presentation] 老年性認知症治療薬の開発に向けて (2009)
  • Author(s): 川原正博
  • Organizer: 都市エリア産学官連携事業 浜辺のセミナー
  • Place of Presentation: 宮崎
  • Year and Date: 2009-09-14
• [Presentation] Analysis of Alternation of A-Asp and L-Asn residures in peptides related to conformational disease (2009)
  • Author(s): Sadakane Y, Konoha K, Kawahara M, Nakagomi K
  • Organizer: International D-amino acid Research
  • Place of Presentation: Awazi Inland, Japan
  • Year and Date: 2009-07-05
• [Presentation] Analysis of Alternation of A-Asp and L-Asn residures in peptides related to conformational disease (2009)
  • Author(s): Sadakane Y, Konoha K, Kawahara M, Nakagomi K
  • Organizer: International D-amino acid Research (IDAR2009)
  • Place of Presentation: Awaji Irland, Japan
  • Year and Date: 2009-07-01
• [Presentation] Carnosine inhibits s-sheet formation of PrP106-126 and protects against its neurotoxicity (2009)
  • Author(s): Kawahara M, T. Nagata, K. Konoha, Y. Sadakane
  • Organizer: International Conference on Alzheimer's disease and related disorders
  • Place of Presentation: Wien
• [Presentation] Carnosine inhibits β-sheet formation of PrP106-126 and protects against its neurot oxicitv (2009)
  • Author(s): Kawahara M, Nagata T, Konoha K, Sadakane Y
  • Organizer: International Conference of Alzheimer's Disease (ICAD2009)
  • Place of Presentation: Wien, Austria
• [Book] Disruption of calcium homeostasis in Alzheimer's disease : role of channel formation byβAmyloid Protein, In "Neurodegenerative Diseases/Book 2" (2011)
  • Author(s): Kawahara M., Koyama H., Ohkawara S., Kato-Negishi M.
• [Book] Disruption of calcium homeostasis in Alzheimer's disease : role of channel formation by β Amyloid Protein In "Neurodegenerative Diseases/Book 2", ISBN 979-953-307-672-9(Ed by Ivana Zach) (2011)
  • Author(s): Kawahara M., Koyama H., Ohkawara S., Kato-Negishi M
  • Publisher: InTech
• [Book] Protective substances against zinc-induced neuronal death after ischemia : carnosine as a target for drug of vascular type of dementia. In Frontiers in CNS Drug Discovery (2010)
  • Author(s): Kawahara M, Konoha K, Tetsuya N and Sadakane Y
  • Publisher: Bentham Science Publishers
• [Book] Quantification of structural alterations of L-Asp and L-Asn residues in peptides related to neuronal disease by reversed-phase HPLC. In D-Amino Acids in chemistry, Life Sciences and Biotechnology (2010)
  • Author(s): Sadakane Y., Konoha K., Kawahara M., Nakagomi K. Hans Bruckner and Noriko Fujii
• [Book] Aluminum and human health : possible link with neurodegenerative disorders. In Metals and Neurodegeneration (2010)
  • Author(s): Kawahara M
• [Book] Metals and Neurodegeneration (Editor : Shile Huang) (2010)
  • Author(s): Kawahara M:
  • Publisher: Aluminum and human health : possible link with neurodegenerative disorders. (Research Signpost)
• [Book] 認知症予防候補物質の探索と単離・構造決定、「薬学分析科学の最前線」、日本薬学会物理系薬学部会・分析化学担当教員会議編 (2009)
  • Author(s): 川原正博、定金豊
  • Publisher: じほう
• [Patent(Industrial Property Rights)] 脳血管性認知症の治療剤および該治療剤を含有する飲食物、補助食品 (2009)
  • Inventor(s): 川原正博、定金豊、木葉敬子
  • Industrial Property Rights Holder: 九州保健福祉大学
  • Patent Publication Number: 2009-249335
  • Filing Date: 2009-10-29