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神経回路形成におけるオートファジー・リソソーム系の役割の分子細胞生物学的解析

Research Project

Project/Area Number 18021019
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionOsaka University

Principal Investigator

小池 正人  Osaka University, 医学糸研究科, 助教 (80347210)

Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 2007: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥3,300,000 (Direct Cost: ¥3,300,000)
Keywordsリソソーム / オートファジー / カテプシン / ダブルノックアウトマウス / 軸索 / spheroid / カテプシンD / カテプシンL / ノックアウトマウス / 二次元電気泳動 / プロテオーム
Research Abstract

カテプシンBとL、カテプシンDとLの生存期間は生後14日未満で死に至るのに対して、カテプシンBとDのダブルノックアウトマウスはその多くが生後23日前後まで生存することが新たに判明した。カテプシンDL、BDのダブルノックアウトマウスではカテプシンBLダブルノックアウトマウスと同様、脳梁等において、spheroidが多数形成され、LC3陽性の顆粒状構造物が蓄積し、電顕的に初期段階のオートファゴソームと類似した構造物の蓄積が確認された。最近ドイツのグループがカテプシンBLダブルノックアウトマウスと対照群のリソソームフラクションを用いて、iTRAQ法によって変化が認められた蛋白を見いだした(Stahl, et. al.,2007,BBA)。彼らは対照群と比べてRab14、Neuron specific gene family member 1/Calcyon、Delta/notch-like EGF-related receptor(DNER)、Carboxypeptidase E、KIAA 1414が約10倍以上増加していると報告したが、いずれも小胞輸送に関わることが知られている。これらのうちRabl4、DNER、CarboxypeptidaseEに対ずる良い抗体が得られたので上記3系統のダブルノックアウトマウスにおいてそれぞれその局在を検討したところ、いずれのマウスにおいても、軸索が変性しspheroid様構造を形成している部位に強く認められることが分かった。以上の結果は、リソゾームタンパク分解酵素の欠損を伴う神経細胞においては、軸索における細胞内輸送が共通して傷害されることを示しており、軸索内でオートファゴソームが蓄積する要因は、リソソームの分解が妨げられるだけでなく、細胞体への輸送そのものが阻害されている可能性が示唆された。

Report

(2 results)
  • 2007 Annual Research Report
  • 2006 Annual Research Report
  • Research Products

    (18 results)

All 2008 2007 2006

All Journal Article (12 results) (of which Peer Reviewed: 8 results) Presentation (6 results)

  • [Journal Article] Inhibition of Autophagy Prevents Hippocampal Pyramidal Neuron Death after Hypoxic-Ischemic Injury.2008

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

      Am. J. Pathol 172

      Pages: 454-469

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Developing Post-Mitotic Mammalian Neurons In Vivo Lacking Apaf-1 Undergo Programmed Cell Death by a Caspase-Independent, Non-Apoptotic Pathway Involving Autophagy.2008

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

      J. Neurosci. 28

      Pages: 1490-1497

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Participation of autophagy in renal ischemia/reperfusion injury.2008

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

      Biochem. Biophys. Res. Commun. 368

      Pages: 300-306

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Lysosomal Degradation of Nuclear DNA by DNase II-like Acid DNase in Cortical Fiber Cells of Mouse Eye Lens.2007

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

      FEBSJ 274

      Pages: 3055-3064

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] RGS18 acts as a negative regulator of osteoclastogenesis by modulating acid-sensing OGR1/NFAT signaling pathway.2007

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

      J Bone Miner Res. 22

      Pages: 1612-20

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Identification of Tim-4 as a phosphatidylserine receptor.2007

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

      Nature 450

      Pages: 435-439

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagydeficient mice.2007

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

      Cell 131

      Pages: 1149-1163

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Generation of a Recombinant Oka Varicella Vaccine Expressing Mumps Virus Hemagglutinin-Neuraminidase Protein as a Polyvalent Live Vaccine.2007

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

      Vaccine 25

      Pages: 8741-8755

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Loss of autophagy in the central nervous system causes neurodegeneration.2006

    • Author(s)
      Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata J., Ueno, T., Koike, M., Uchiyama, Y., Kominami, E., Tanaka, K.
    • Journal Title

      Nature 441巻15号

      Pages: 880-884

    • Related Report
      2006 Annual Research Report
  • [Journal Article] RANKL-induced expression of tetraspanin CD9 in lipid raft membrane microdomain is essential for cell fusion during osteoclastogenesis.2006

    • Author(s)
      Ishii, M., Iwai K., Koike, M., Ohshima S., Kudo-Tanaka E., Ishii T., Mima T., Katada, Y., Miyatake, K., Uchiyama, Y., Saeki, Y.
    • Journal Title

      J Bone Miner Res. 21巻6号

      Pages: 965-976

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Sleeping Beauty Transposon-based phenotypic analysis in mice : Lack of Arpc3 results in defective trophectoderm outgrowth.2006

    • Author(s)
      Yae, K., Keng VW., Koike, M., Yusa, K., Kouno, M., Uno, Y., Kondoh, G., Gotow, T., Uchiyama, Y., Horie, K., Takeda, J.
    • Journal Title

      Mol. Cell Biol. 26巻16号

      Pages: 6185-6196

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Effects of RNA interference of Atg4B on the limited proteolysis of LC3 in PC12 cells and expression of Atg4B in various rat tissues.2006

    • Author(s)
      Yoshimura, K., Shibata M., Koike M., Gotoh, K., Fukaya, M., Watanabe, M., Uchiyama, Y.
    • Journal Title

      Autophagy 2巻3号

      Pages: 200-208

    • Related Report
      2006 Annual Research Report
  • [Presentation] Selective antophagy regulates formation of cytoplasmic inclusions.2007

    • Author(s)
      Komatsu et. al.
    • Organizer
      第30回日本分子生物学会年会第80回日本生化学会大会合同大会
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      2007-12-13
    • Related Report
      2007 Annual Research Report
  • [Presentation] Involvement of autophagy in neurons of the hippocampus afert adult mouse hypoxicischemic infury.2007

    • Author(s)
      Koike et. al.
    • Organizer
      76th Annual Meeting Society for Neuroscience
    • Place of Presentation
      サンディエゴ
    • Year and Date
      2007-11-06
    • Related Report
      2007 Annual Research Report
  • [Presentation] カテプシンD欠損に伴うリソソーム蓄積症の病態形成について2007

    • Author(s)
      小池正人, ら
    • Organizer
      第50回日本神経化学会大会、第17回日本神経回路学会大会合同大会
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      2007-09-11
    • Related Report
      2007 Annual Research Report
  • [Presentation] 中枢神経特異的カテプシンD欠損による神経性セロイドリボフスチン蓄積症類似症状の誘導2007

    • Author(s)
      柴田昌宏, ら
    • Organizer
      第50回日本神経化学会大会、第17回日本神経回路学会大会合同大会
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      2007-09-11
    • Related Report
      2007 Annual Research Report
  • [Presentation] Posssible roles of LC3, ubiquitin, and P62 in the accumulation of lysosomes in neurons deficient in Cathepsin D.2007

    • Author(s)
      Koike et. al.
    • Organizer
      7th IBRO World Congress of Neuroscience
    • Place of Presentation
      メルボルン
    • Year and Date
      2007-07-14
    • Related Report
      2007 Annual Research Report
  • [Presentation] A mouse with low expression of Cathepsin D is a model animal of neuronal Ceroid Lipofuscinosis.2007

    • Author(s)
      Shibata et. al.
    • Organizer
      7th IBRO World Congress of Neuroscience
    • Place of Presentation
      メルボルン
    • Year and Date
      2007-07-14
    • Related Report
      2007 Annual Research Report

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Published: 2006-04-01   Modified: 2018-03-28  

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