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Endoplasmicreticulum(ER)stress and Parkinsonism

Research Project

Project/Area Number 17500226
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Nerve anatomy/Neuropathology
Research InstitutionKanazawa University

Principal Investigator

KITAO Yasuko  Kanazawa University, Graduate School of Medical Science, Assistant Professor (00019613)

Co-Investigator(Kenkyū-buntansha) OGAWA Satoshi  Kanazawa University, Graduate School of Medical Science, Professor (90283746)
HORI Osamu  Kanazawa University, Graduate School of Medical Science, Associate Professor (60303947)
Project Period (FY) 2005 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥3,730,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2006: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
KeywordsParkinson's disease / stress / endoplasmic reticulum / neuronal cell death / パーキンソ二ズム / パエル受容体 / 小胞体ストレス / 黒質線条体神経 / ドパミン / パーキンソニズム / ドパミン「
Research Abstract

Selective loss of dopaminergic neurons is the final common pathway in Parkinson's disease, the second most common neurodegenerative disorder. Selective neuronal expression of Pael-R(Parkin associated endothelin-like receptor)in mouse brain was achieved by injecting adenoviral vectors carrying a modified neuron-specific promoter and Cre-recombinase into the striatum. Upregulation of Pael-Receptor in the substantia nigra pars compacts (SNpc) of mice by retrograde infection induced endoplasmic reticulum(ER) stress lead to decreased levels of tyrosine hydroxylase and death of dopaminergic neurons. Neuronal cell death was not observed in the other areas of the brain projecting to/from the SNpc. The role of ER stress in dopaminergic neuronal vulnerability was highlighted by their decreased survival in mice deficient in the ubiquitin-protein ligase Parkin and the ER chaperone ORP150(150 kDa oxygen regulated protein), compared with their robust survival consequent to overexpression of either P … More arkin or an ER chaperone, 78 kDa glucose regulated protein (GRP78). Dopamine-related toxicity was also a key factor, as a dopamine synthetase inhibitor blocked neuronal death in parkin null mice. These data suggest a model in which ER- and dopamine-related slam are major contributors to decreased viability of dopaminergic neurons in a setting relevant to Parkinson's disease.
FENIB (familial encephalopathy with neuroserpin inclusion bodies)is caused by intracellular accumulation/polymerization of mutant neuroserpins. Transgenic rats overexpressing megsin (Tg meg), a newly identified serine protease inhibitor (serpin), demonstrated intraneuronal periodic-acid Schiff (PAS)-positive inclusions distributed throughout deeper layers of cerebral cortex, CA1 of the hippocampus, and substantia nigra. Hippocampal extracts from Tg meg rats showed increased expression of ER stress proteins, and activation of caspases-12 & -3, associated with decreased neuronal density. Enhanced ER stress was also observed in dopaminergic neurons in the substantia nigra, in parallel with decreased neuronal viability and motor coordination. In each case, PAS-positive inclusions were also positive for megsin. These data suggest that overexpression of megsin results in ER stress, eventuating in the formation of PAS-positive inclusions. Tg meg rats provide a novel model relevant to FENIB in which accumulation of serpins in the ER induces selective dysfunction/loss of specific neuronal populations. Less

Report

(4 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • 2005 Annual Research Report
  • Research Products

    (30 results)

All 2007 2006 2005

All Journal Article (22 results) (of which Peer Reviewed: 11 results) Presentation (4 results) Book (1 results) Patent(Industrial Property Rights) (3 results) (of which Overseas: 1 results)

  • [Journal Article] Pael receptor induces death of dopaminergic neurons in the substantianigra via endoplasmic reticulum stress and dopamine toxicity, which is enhanced under condition of parkin inactivation.2007

    • Author(s)
      Kitao Y, et. al.
    • Journal Title

      Human Mol. Genetics. 16(1)

      Pages: 50-60

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Pael receptor induces death of dopaminergic neurons in the substantia nigra via endoplasmic reticulum stress and dopamine toxicity, which is enhanced under condition of parkin inactivation2007

    • Author(s)
      Kitao, Y., Imai, Y., Ozawa, K., Kataoka, A., Ikeda, T., Soda, M., Namekawa, K., Kiyama, H., Stern, DM., Hori, O., Wakamatsu, K., Ito, S., Itohara, S., Takahashi, R., Ogawa, S
    • Journal Title

      Human Mol. Genetics 16(1)

      Pages: 50-60

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Methoxyflavones protect cells against endoplasmic reticulum (ER) stress and neurotoxin.2007

    • Author(s)
      Takano K, et. al.
    • Journal Title

      Am. J. Physiol. Cell Physiol. 292(1)

      Pages: 353-361

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Vaticanol B, a resveratrol tetramer, regulates endoplasmic reticulum (ER) stress and inflammation.2007

    • Author(s)
      Tabata Y, et. al.
    • Journal Title

      Am. J. Physiol. Cell Physiol. 293(1)

      Pages: 411-418

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Adibenzoylmethane (DBM) derivative protects dopaminergic neurons against both oxidative stress and endoplamic reticulum (ER) stress.2007

    • Author(s)
      Takano K, et. al.
    • Journal Title

      Am. J. Physiol. Cell Physiol. 293(6)

      Pages: 1884-1894

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pael receptor induces death of dopaminergic neurons in the substantianigra via endoplasmic reticulum stress and dopamine toxicity, which isenhanced under condition of parkin inactivation.2007

    • Author(s)
      Kitao Y, et. al.
    • Journal Title

      Human Mol. Genetics. 16(1)

      Pages: 50-60

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hypoxia-mediated induction of heme oxygenase type I and carbon monoxde release from astrocytes protects nearby cerebral neurons from hypoxia-mediated apoptosis.2007

    • Author(s)
      Imuta N, et. al.
    • Journal Title

      Antioxid Redox Signal. 9

      Pages: 573-587

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ischemia-induced neuronal cell death and stress response.2007

    • Author(s)
      Ogawa S, et. al.
    • Journal Title

      Antioxid Redox Signal. 9

      Pages: 1884-1894

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Does ORP150/HSP12A protect dopaminergic neurons against MPTP/MPP(+)-induced neurotoxicity?2007

    • Author(s)
      Kitao Y, et. al.
    • Journal Title

      Antioxid Redox Signal. 9

      Pages: 589-595

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Anovel inhibitor of advanced glycation and endoplasmic reticulum stress reduces infarct volume in rat focal cerebral ischemia.2007

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

      Brain Res 1183

      Pages: 124-37

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Methoxyflavones protect cells against endoplasmic reticulum (ER) stress and neurotoxin.2007

    • Author(s)
      堀, 北尾, 小川, ほか
    • Journal Title

      Am. J. Physiol. 292(1)

    • NAID

      40015637308

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Pael receptor induces death of dopaminergic neurons in the substantia nigra via endoplasmic reticulum stress and dopamine toxicity, which is enhanced under condition of parkin inactivation.2007

    • Author(s)
      北尾, 堀, 小川, ほか
    • Journal Title

      Human Mol. Genetics. 16(1)

      Pages: 50-60

    • Related Report
      2006 Annual Research Report
  • [Journal Article] A rat model of human FENIB(familial encephalopathy with neuroserpin inclusion bodies). Biochem Biophys Res Commun2006

    • Author(s)
      Takano, et. al.
    • Journal Title

      Biochem Biophys Res Commun. 346

      Pages: 1040-1047

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Deletion of SERP1/RAMP4, a component of the endoplasmic reticulum(ER)translocation sites, leads to ER stress2006

    • Author(s)
      Hori, et. al.
    • Journal Title

      Mol. Cell. Biol. 26

      Pages: 4257-67

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Deletion of SERP1/RAMP4, a component of the endoplasmic reticulum(ER)translocation sites, leads to ER stress2006

    • Author(s)
      Hori, O., Miyazaki, M., Tamatani, T., Ozawa, K., Takano, K., Okabe, M., Ikawa, M., Hartmann, M., Mai, P., Stern, M., Kitao, Y., Ogawa, S
    • Journal Title

      Mol. Cell. Biol 26

      Pages: 4257-67

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] A rat model of human FENIB(familial encephalopathy with neuroserpin inclusion bodies)2006

    • Author(s)
      Takano, K., Kitao, Y., Inagi, R., Momoi, T., Matsuyama, T., Miyata, T., Yoneda, Y., Iso, H., Stern, DM., Hon, O., Ogawa, S
    • Journal Title

      Biochem Biophys Res Commun 346

      Pages: 1040-1047

    • NAID

      120000809734

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Deletion of SERP1/RAMP4, a component of the endoplasmic reticulum (ER) translocation sites, leads to ER stress.2006

    • Author(s)
      堀, 北尾, 小川, ほか
    • Journal Title

      Mol. Cell. Biol. 26

      Pages: 4257-4267

    • Related Report
      2006 Annual Research Report
  • [Journal Article] A rat model of human FENIB (familial encephalopathy with neuroserpin inclusion bodies).2006

    • Author(s)
      堀, 北尾, 小川, ほか
    • Journal Title

      Biochem Biophys Res Commun. 346

      Pages: 1040-1047

    • NAID

      120000809734

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Involvement of endoplasmic reticulum stress in insulin resistance and diabetes.2005

    • Author(s)
      中谷, 小川ほか
    • Journal Title

      J Biol Chem. 280

      Pages: 847-851

    • Related Report
      2005 Annual Research Report
  • [Journal Article] RA410/Sly1 suppresses MPP+ and 6-hydroxydopamine induced cell death in SH-SY5Y cells.2005

    • Author(s)
      坂東, 小川ほか
    • Journal Title

      Neurobiology of Disease 18

      Pages: 143-151

    • Related Report
      2005 Annual Research Report
  • [Journal Article] The ER chaperone 150 kDa Oxygen Regulated Protein (ORP150) improves insulin resistance in Type 2 Diabetes Mellitus.2005

    • Author(s)
      小澤, 北尾ほか
    • Journal Title

      Diabetes. 54

      Pages: 657-663

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Involvement of endoplasmic reticulum(ER) stress in podocyte injury associated with a novel transgenic model of serpinopathy.2005

    • Author(s)
      稲城, 北尾ほか
    • Journal Title

      Kidney International. 68

      Pages: 2639-2650

    • Related Report
      2005 Annual Research Report
  • [Presentation] Vaticanol B, a resveratrol tetramer, regulates endoplasmic reticulum (ER) stress and inflammation2007

    • Author(s)
      Miura H, et. al.
    • Organizer
      第30回日本分子生物学会年会、第80回目本生化学会大会合同大会
    • Place of Presentation
      横浜
    • Year and Date
      2007-12-11
    • Related Report
      2007 Annual Research Report
  • [Presentation] Ascreening system for compounds to protect cells against endoplasmic reticulum (ER) stress2007

    • Author(s)
      Hori O
    • Organizer
      第6回動物実験代替法世界大会
    • Place of Presentation
      東京
    • Year and Date
      2007-08-25
    • Related Report
      2007 Annual Research Report
  • [Presentation] OVEREXPRESSION OF MEGSIN INDUCES NEURONAL DEGENERATION: ROLE OF THE ENDOPLASMIC RETICULUM STRESS RESPONSE2005

    • Author(s)
      Takano K, et. al.
    • Organizer
      The American Society for Cell Biology
    • Place of Presentation
      サンフランシスコ
    • Year and Date
      2005-12-12
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] OVEREICPRESSION OF MEGSIN INDUCES NEURONAL DEGENERATION : ROLE OF THE ENDOPLASMIC RETICULUM STRESS RESPONSE2005

    • Author(s)
      Takano, K., et. al.
    • Organizer
      The American Society for Cell Biology
    • Place of Presentation
      San Francisco
    • Year and Date
      2005-12-12
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Book] 生化学 特集:シナプスから核へ-核からシナプスへ 「神経細胞死とストレス関連遺伝子の発現」2006

    • Author(s)
      小川 智、堀 修
    • Total Pages
      6
    • Publisher
      日本生化学会
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Patent(Industrial Property Rights)] 小胞体ストレス制御物質とそれを有効成分とする医薬組成物2007

    • Inventor(s)
      堀修他
    • Industrial Property Rights Holder
      明治乳業
    • Filing Date
      2007-05-25
    • Related Report
      2007 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] ピリミジン誘導剤を有効成分とする医薬組成物2007

    • Inventor(s)
      堀修他
    • Industrial Property Rights Holder
      金沢大学明治乳業
    • Filing Date
      2007-11-27
    • Related Report
      2007 Annual Research Report
  • [Patent(Industrial Property Rights)] 小胞体ストレス制御化合物とそれを有効成分とする医薬組成物2006

    • Inventor(s)
      堀 修、小川 智, 他
    • Industrial Property Rights Holder
      金沢大学・明治乳業
    • Filing Date
      2006-05-25
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary

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Published: 2005-04-01   Modified: 2016-04-21  

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