• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Involvement of novel ubiquitin ligases in the pathogenic mechanism of Alzheimer's disease and drug discovery for fundamental therapeutic agent

Research Project

Project/Area Number 24300135
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Neurochemistry/Neuropharmacology
Research InstitutionKurume University (2013-2015)
Yokohama College of Pharmacy (2012)

Principal Investigator

Nomura Yasuyuki  久留米大学, 医学部, 教授 (00034041)

Co-Investigator(Kenkyū-buntansha) Sobue Gen  名古屋大学, 医学系研究科, 特任教授 (20148315)
Okuma Yasunobu  千葉科学大学, 薬学部, 教授 (20127939)
Kitamura Yoshihisa  立命館大学, 薬学部, 教授 (60195295)
Tomobe Koji  横浜薬科大学, 薬学部, 准教授 (80460286)
Kaneko Masayuki  広島大学, 医歯薬保健学研究院(医), 准教授 (10322827)
Co-Investigator(Renkei-kenkyūsha) Ishigaki Shinsuke  名古屋大学, 医学系研究科, 特任助教 (40378170)
Takata Kazuyuki  京都薬科大学, 薬学部, 准教授 (10434664)
Kawada Koichi  千葉科学大学, 薬学部, 講師 (30581631)
Project Period (FY) 2012-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000)
Fiscal Year 2014: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2013: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2012: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
Keywordsアルツハイマー病 / ユビキチンリガーゼ / APP / アミロイドβ / ERAD / 酸化ストレス / γ-セクレターゼ / 膜輸送 / RNF19B / エンドソーム / 小胞体 / 小胞体ストレス / EDAD / 神経細胞 / RNF19B / Dorfin / HRD1 / 質量分析 / ノックアウトマウス
Outline of Final Research Achievements

We found that the ubiquitin ligase HRD1 is involved in degradation of amyloid precursor protein (APP), which is processed into β-amyloid, the responsible protein for Alzheimer’s disease (AD). Interestingly, HRD1 protein is reduced in the postmortem cerebral cortex of AD patients, possibly because of its protein insolubilization. In this study, we demonstrated the involvement of oxidative stress in HRD1 insolubilization. We also found that ubiquitin ligases, Dorfin (RNF19A) and RNF19B, are involved in Aβ generation through a different mechanism from that of HRD1. In this study, we demonstrated that Dorfin and RNF19B regulate APP processing by γ-secretase through APP trafficking to the lysosome.

Report

(5 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • Research Products

    (44 results)

All 2016 2015 2014 2013 2012 Other

All Journal Article (14 results) (of which Peer Reviewed: 14 results,  Acknowledgement Compliant: 4 results,  Open Access: 4 results) Presentation (26 results) (of which Invited: 5 results) Book (4 results)

  • [Journal Article] Evaluation of synthetic naphthalene derivatives as novel chemical chaperones that mimic 4-phenylbutyric acid2015

    • Author(s)
      Mimori, S., Koshikawa, Y., Mashima, Y., Mitsunaga, K., Kawada, K., Kaneko, M., Okuma, Y., Nomura, Y., Murakami, Y., Kanzaki, T., Hamana, H.
    • Journal Title

      Bioorganic and Medicinal Chemistry Letters

      Volume: 25 Pages: 811-814

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Possible involvement of endoplamic reticulum stress in the pathogenesis of Alzheimer's disease2015

    • Author(s)
      Hosoi, T., Nomura, J., Ozawa, K., Nishi, A., Nomura, Y.
    • Journal Title

      Endoplasmic Reticulum Stress in Diseases

      Volume: 2 Issue: 1 Pages: 107-116

    • DOI

      10.1515/ersc-2015-0008

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Pharmacological Studies on Neurodegenerative Diseases Focusing on Refolding and Degradation of Unfolded Proteins in the Endoplasmic Reticulum2014

    • Author(s)
      野村靖幸
    • Journal Title

      YAKUGAKU ZASSHI

      Volume: 134 Issue: 4 Pages: 537-543

    • DOI

      10.1248/yakushi.13-00252

    • NAID

      130003391203

    • ISSN
      0031-6903, 1347-5231
    • Year and Date
      2014-04-01
    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effects of oxidative stress on the solubility of HRD1, a ubiquitin ligase implicated in Alzheimer's disease2014

    • Author(s)
      Saito R., Kaneko M., Kitamura Y.,Takata K., Kawada K., Okuma Y. and Nomura Y.
    • Journal Title

      PLos One

      Volume: 9

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Aberrant neuronal differentiation and inhibition of dendrite outgrowth resulting from endoplasmic reticulum stress.2014

    • Author(s)
      Kawada K, Iekumo T, Saito R, Kaneko M, Mimori S, Nomura Y, Okuma Y
    • Journal Title

      Journal of neuroscience research

      Volume: 0 Issue: 9 Pages: 0-0

    • DOI

      10.1002/jnr.23389

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibition of inducible nitric oxide synthase and interleukin-1β expression by tunicamycin in cultured glial cells exposed to lipopolysaccharide2014

    • Author(s)
      Noguchi J., Takakuwa M., Honda M., Okuma Y., Nomura Y. and Ozawa K.
    • Journal Title

      Brain Research

      Volume: 1558 Pages: 11-17

    • DOI

      10.1016/j.brainres.2014.02.035

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Effects of oxidative stress on the solubility of HRD1, a ubiquitin ligaseimplicated in Alzheimer's disease2014

    • Author(s)
      Saito R., Kaneko M., Kitamura Y., et al.
    • Journal Title

      PLoS ONE

      Volume: 9巻 Issue: 5 Pages: 94576-94576

    • DOI

      10.1371/journal.pone.0094576

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibition of post-translational N-glycosylation by HRD1 that controls the fate of ABCG5/8 transporter.2014

    • Author(s)
      Suzuki S, Shuto T, Sato T, Kaneko M, Takada T, Suico MA, Cyr DM, Suzuki H, Kai H
    • Journal Title

      Scientific reports

      Volume: 4 Issue: 1 Pages: 4258-4258

    • DOI

      10.1038/srep04258

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 4-Phenylbutyric acid protects against neuronal cell death by primarily acting as a chemical chaperone rather than histone deacetylase inhibitor.2013

    • Author(s)
      Mimori S, Ohtaka H, Koshikawa Y, Kawada K, Kaneko M, Okuma Y, Nomura Y, Murakami Y, Hamana H
    • Journal Title

      Bioorganic & medicinal chemistry letters

      Volume: 23 Issue: 21 Pages: 6015-6018

    • DOI

      10.1016/j.bmcl.2013.08.001

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Discovery of Synthetic Methoxy-substituted 4-Phenylbutyric Acid Derivatives as Chemical Chaperones2013

    • Author(s)
      Mimori S, Okuma Y, Kaneko M, Kawada K, Nomura Y, Murakami Y and Hamana H
    • Journal Title

      Chemistry Letters

      Volume: 42 Issue: 9 Pages: 1051-1052

    • DOI

      10.1246/cl.130419

    • NAID

      10031194338

    • ISSN
      0366-7022, 1348-0715
    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Endoplasmic Reticulum Stress and Parkinson’s Disease: The Role of HRD1 in Averting Apoptosis in Neurodegenerative Disease2013

    • Author(s)
      Omura T, Kaneko M, Okuma Y, Matsubara K, and Nomura Y
    • Journal Title

      Oxidative Medicine and Cellular Longevity

      Volume: 2013 Pages: 239854-239854

    • DOI

      10.1155/2013/239854

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Molecular Pharmacological Studies on the Protection Mechanism against Endoplasmic Reticulum Stress-induced Neurodegenerative Disease2012

    • Author(s)
      Kaneko M
    • Journal Title

      YAKUGAKU ZASSHI

      Volume: 132 Issue: 12 Pages: 1437-1442

    • DOI

      10.1248/yakushi.12-00249

    • NAID

      130002489541

    • ISSN
      0031-6903, 1347-5231
    • Year and Date
      2012-12-01
    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Activation of OASIS family, ER stress transducers, is dependent on its stabilization2012

    • Author(s)
      Kondo S, Hino SI, Saito A, Kanemoto S, Kawasaki N, Asada R, Izumi S, Iwamoto H, Oki M, Miyagi H, Kaneko M, Nomura Y, Urano F and Imaizumi K
    • Journal Title

      Cell Death Differ

      Volume: 19 Issue: 12 Pages: 1939-1949

    • DOI

      10.1038/cdd.2012.77

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] STT3B-dependent posttranslational N-glycosylation as a surveillance system for secretory protein.2012

    • Author(s)
      Sato T., et.al.
    • Journal Title

      Molecular Cell

      Volume: 47(1) Issue: 1 Pages: 99-110

    • DOI

      10.1016/j.molcel.2012.04.015

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Presentation] 4-フェニル酪酸およびその誘導体の小胞体ストレスに対する神経保護作用2016

    • Author(s)
      大熊康修、三森盛亮、大高泰靖、川田浩一、金子雅幸、神埼哲人、野村靖幸
    • Organizer
      第89回日本薬理学会
    • Place of Presentation
      (パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-03-09
    • Related Report
      2015 Annual Research Report
  • [Presentation] 自閉症スペクトラム症における小胞体ストレス付加と神経成熟異常2015

    • Author(s)
      家雲高哲、川田浩一、三森盛亮、野村靖幸、大熊康修
    • Organizer
      第45回日本神経精神薬理学会・第37回日本生物学的精神医学会
    • Place of Presentation
      タワーホール船堀(東京都江戸川区)
    • Year and Date
      2015-09-24
    • Related Report
      2015 Annual Research Report
  • [Presentation] Expression of ubiquitin ligases with transmembrane domain in the brain2015

    • Author(s)
      金子雅幸、呉艶、高井知子、野村靖幸、今泉和則
    • Organizer
      第58回日本神経化学会大宮大会
    • Place of Presentation
      大宮ソニックシティ(さいたま市)
    • Year and Date
      2015-09-23
    • Related Report
      2015 Annual Research Report
  • [Presentation] 脳の働き、認知症と薬の作用2015

    • Author(s)
      野村靖幸
    • Organizer
      日本杜仲研究会第10回定期大会
    • Place of Presentation
      東京国際フォーラム(東京都千代田区)
    • Year and Date
      2015-07-25
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] 小胞体に関連するユビキチンリガーゼの生理機能2015

    • Author(s)
      金子雅幸
    • Organizer
      日本薬学会第135年会
    • Place of Presentation
      兵庫医療大学、神戸市
    • Year and Date
      2015-03-26 – 2015-03-29
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] 小胞体ストレスによる神経成熟異常と神経発達障害2015

    • Author(s)
      川田浩一、家雲高哲、金子雅幸、野村靖幸、大熊康修
    • Organizer
      日本薬学会第135年会
    • Place of Presentation
      兵庫医療大学、神戸市
    • Year and Date
      2015-03-26
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] 小胞体に局在するユビキチンリガーゼの発現分布2015

    • Author(s)
      呉艶、今泉和則、野村靖幸、金子雅幸
    • Organizer
      第88回日本薬理学会
    • Place of Presentation
      名古屋国際会議場、名古屋市
    • Year and Date
      2015-03-18 – 2015-03-20
    • Related Report
      2014 Annual Research Report
  • [Presentation] The endoplasmic reticulum stress may contribute to the pathogenesis of the autism spectrum disorders2014

    • Author(s)
      Kawada K., Iekumo T., Saito R., Mimori S., Nomura Y. and Okuma Y.
    • Organizer
      Collegium Internationale Neuro-Psychopharmacologium 2014
    • Place of Presentation
      Vancouver, Canada
    • Year and Date
      2014-06-22 – 2014-06-26
    • Related Report
      2014 Annual Research Report
  • [Presentation] Studies of themechanism of action in protective effect against neuronal cell death of 4-phenylbutyrate and its derivatives for therapeutic agents of neurodegenerative disease2014

    • Author(s)
      Mimori S., Ohtake H., Kawada K., Kaneko M., Nomura Y., Okuma Y., Murakami Y. and Hamana H.
    • Organizer
      Collogium Internationale Neuro-Psychopharamcologium 2014
    • Place of Presentation
      Vancouver, Canada
    • Year and Date
      2014-06-22 – 2014-06-26
    • Related Report
      2014 Annual Research Report
  • [Presentation] A novel therapeutic target against Alzheimer's disease: HRD1 as endolplasmic reticulum stress-related ubiquitin ligase2014

    • Author(s)
      Nomura Y, Kaneko M, Okuma Y, Kitamura Y, Takata Y, Nishi A
    • Organizer
      13th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy
    • Place of Presentation
      Geneve, Switzerland
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] ユビキチンリガーゼDor丘nがAβ産生に関与する可能性2013

    • Author(s)
      山森正嗣, 金子雅幸, 高野智喜, 川田浩一, 野村靖幸, 大熊康修
    • Organizer
      日本薬学会第133年会
    • Place of Presentation
      パシフィコ横浜(横浜)
    • Year and Date
      2013-03-29
    • Related Report
      2012 Annual Research Report
  • [Presentation] 小胞体ストレスはユビキチンリガーゼHRD1を介して神経成熟を制御する2013

    • Author(s)
      川田浩一, 金子雅幸, 斎藤僚, 野村靖幸, 大熊康修
    • Organizer
      第86回日本薬理学会年会
    • Place of Presentation
      福岡国際会議場(福岡)
    • Year and Date
      2013-03-22
    • Related Report
      2012 Annual Research Report
  • [Presentation] 酸化ストレスによるユビキチンリガーゼHRD1の不溶化がアルツハイマー病の病態形成に関与する可能性2013

    • Author(s)
      斎藤僚, 金子雅幸, 川田浩一, 野村靖幸, 大熊康修
    • Organizer
      第86回日本薬理学会年会
    • Place of Presentation
      福岡国際会議場(福岡)
    • Year and Date
      2013-03-21
    • Related Report
      2012 Annual Research Report
  • [Presentation] ユビキチンリガーゼHRD1とアルツハイマー病2012

    • Author(s)
      金子雅幸
    • Organizer
      第7回小胞体ストレス研究会
    • Place of Presentation
      広島大学(広島)(招待講演)
    • Year and Date
      2012-11-09
    • Related Report
      2012 Annual Research Report
  • [Presentation] 小胞体ストレスによる突起伸長抑制に対するユビキチンリガーゼHRD1の関与2012

    • Author(s)
      川田浩一, 金子雅幸, 佐藤亜紗美, 野村靖幸, 大熊康修
    • Organizer
      第35回日本神経科学大会
    • Place of Presentation
      名古屋国際会議場(名古屋)
    • Year and Date
      2012-09-18
    • Related Report
      2012 Annual Research Report
  • [Presentation] ユビキチンリガーゼDorfinがCTFβのモノユビキチン化に影響してAβ産生に関与する可能性2012

    • Author(s)
      高野智喜, 山森正嗣, 金子雅幸, 野村靖幸, 大熊康修
    • Organizer
      第126回薬理関東部会
    • Place of Presentation
      北里大学(東京)
    • Year and Date
      2012-07-15
    • Related Report
      2012 Annual Research Report
  • [Presentation] アミロイド前駆体タンパク質APP代謝とユビキチンリガーゼ

    • Author(s)
      金子雅幸,大熊康修,野村靖幸
    • Organizer
      生体機能と創薬シンポジウム2013
    • Place of Presentation
      福岡
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] ユビキチンリガーゼDorfinがアミロイド前駆体タンパク質輸送を介したアミロイドβ産生に関与する可能性

    • Author(s)
      金子雅幸,山森正嗣,保住功,野村靖幸,大熊康修
    • Organizer
      Neuro2013
    • Place of Presentation
      京都
    • Related Report
      2013 Annual Research Report
  • [Presentation] ユビキチンリガーゼRNF19BおよびDorfinの複合体形成の可能性

    • Author(s)
      野口尚樹,金子雅幸,山森正嗣,保住功,大熊康修,野村靖幸
    • Organizer
      次世代を担う創薬・医療薬理シンポジウム2013
    • Place of Presentation
      熊本
    • Related Report
      2013 Annual Research Report
  • [Presentation] 小胞体関連分解構成因子SEL1Lの発現抑制による神経分化の抑制

    • Author(s)
      齋藤僚,川田浩一,金子雅幸,野村靖幸,大熊康修
    • Organizer
      次世代を担う創薬・医療薬理シンポジウム2013
    • Place of Presentation
      熊本
    • Related Report
      2013 Annual Research Report
  • [Presentation] 小胞体ストレスによる神経突起の伸張抑制

    • Author(s)
      川田浩一,家雲髙哲,齋藤 僚,金子雅幸,野村靖幸,大熊康修
    • Organizer
      次世代を担う創薬・医療薬理シンポジウム2013
    • Place of Presentation
      熊本
    • Related Report
      2013 Annual Research Report
  • [Presentation] Aβ産生機構に関与するユビキチンリガーゼの同定

    • Author(s)
      金子雅幸
    • Organizer
      第8回小胞体ストレス研究会
    • Place of Presentation
      金沢
    • Related Report
      2013 Annual Research Report
  • [Presentation] ユビキチンリガーゼDorfinとRNF19Bがアミロイド前駆体タンパク質輸送を介したアミロイドβ産生に関与する可能性

    • Author(s)
      金子雅幸,山森正嗣,野口尚樹,齋藤僚,保住功,大熊康修,野村靖幸
    • Organizer
      第87回日本薬理学会年会
    • Place of Presentation
      仙台
    • Related Report
      2013 Annual Research Report
  • [Presentation] ユビキチンリガーゼHRD1の不溶化機構における酸化ストレスの影響

    • Author(s)
      齋藤僚,金子雅幸,川田浩一,野村靖幸,大熊康修
    • Organizer
      第87回日本薬理学会年会
    • Place of Presentation
      仙台
    • Related Report
      2013 Annual Research Report
  • [Presentation] 自閉症における小胞体ストレスの関与

    • Author(s)
      川田浩一,家雲高哲,齋藤僚,金子雅幸,野村靖幸,大熊康修
    • Organizer
      第87回日本薬理学会年会
    • Place of Presentation
      仙台
    • Related Report
      2013 Annual Research Report
  • [Presentation] 自閉症における小胞体ストレスによる神経分化異常の関与

    • Author(s)
      家雲高哲,川田浩一,齋藤僚,野村靖幸,大熊康修
    • Organizer
      日本薬学会第134年会
    • Place of Presentation
      熊本
    • Related Report
      2013 Annual Research Report
  • [Book] 四季の生薬2016

    • Author(s)
      野村靖幸
    • Total Pages
      439
    • Publisher
      薬事日報社
    • Related Report
      2015 Annual Research Report
  • [Book] くすりと健康2013

    • Author(s)
      野村靖幸
    • Total Pages
      247
    • Publisher
      薬事日報社
    • Related Report
      2013 Annual Research Report
  • [Book] The Senescence-accelerated Mouse (SAM): Achievements and Future Directions2013

    • Author(s)
      Hosoi T, Nomura J, Okuma Y, Nomura Y
    • Publisher
      Elsevier
    • Related Report
      2013 Annual Research Report
  • [Book] The Senescence-accelerated Mouse (SAM): Achievements and Future Directions2013

    • Author(s)
      Tomobe K, Isobe M, Nomura Y
    • Publisher
      Elsevier
    • Related Report
      2013 Annual Research Report

URL: 

Published: 2012-04-24   Modified: 2019-07-29  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi