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パーキンソン病におけるパエル受容体の病態的役割の解明

Research Project

Project/Area Number 18023020
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

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

Principal Investigator

高橋 良輔  Kyoto University, 医学研究科, 教授 (90216771)

Co-Investigator(Kenkyū-buntansha) 金子 鋭  財団法人田附興風会, 医学研究所・第4研究部, 主任研究員 (70303815)
王 華芹  京都大学, 医学研究科, 客員研究員 (50391884)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥8,600,000 (Direct Cost: ¥8,600,000)
Fiscal Year 2007: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 2006: ¥4,300,000 (Direct Cost: ¥4,300,000)
KeywordsPael-R / Parkin / ノックアウトマウス / トランスジェニックマウス / 小胞体ストレス / ドーパミン / BiP / CHOP / AR-JP / ユビキチンリガーゼ / トランスジェニックマス / ドパミン / ミトコンドリア / 酸化的ストレス
Research Abstract

AR-JPモデルマウスを作出する目的でニューロン特異的なプロモーター(PrionおよびPDGFプロモーター)を用いてPael-Rトランスジェニックマウス(Pael-R Tg)を作製した。Pael-R Tgでは軽度ながら、12ヶ月から選択的に黒質ドーパミンニューロンの脱落が認められた。この結果を踏まえ、今年度はPael-R-TgにParKin-KOマウスを掛け合わせた二重変異マウス(Pael-R-Tg/Parkin-KO)を作成した。二重変異マウスでは生後6ケ月から黒質および青斑核に細胞脱落が観察されはじめて徐々に進行し、24ヶ月ではヘテロ接合型マウスでは20%、ホモ接合型マウスでは40%の細胞死が観察された。これらの変化はカテコールアミン作動性ニューロンに特異的であり、海馬のニューロンには細胞死がみられなかった。また、黒質では小胞体シャペロンBiP、転写因子CHOP、スプライス型のXBP-1、活性化型カスパーゼ12のmRNA、蛋白質レベルでの増加が観察され、これらが黒質ではドーパミンニューロンでの変化を主として反映していることが免疫組織学的に確かめられた。さらに18ヶ月齢からは、ミトコンドリアの複合体Iの活性が特異的に低下することも見出した。酸化的ストレスのマーカーとなるカルボニル化蛋白質の量は大脳皮質では増えず、変性の生じる黒質で顕著に認められた。また線条体のドーパミン量は6ヶ月齢では増えるが、その後はドーパミン細胞死に相関して減少に転じた。このマウスではPael-Rの蓄積による小胞体ストレスによりカテコールアミン特異的細胞死が誘発され、その過程でドーパミンやミトコンドリアの活性低下による酸化的ストレスによって変性が加速するメカニズムが推測される。以上よりこの二重変異マウス(Pael-R-Tg/Parkin-KO)はAR-JPのはじめてのよいモデルになるものと思われる。

Report

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

    (28 results)

All 2008 2007 2006 Other

All Journal Article (22 results) (of which Peer Reviewed: 7 results) Presentation (5 results) Remarks (1 results)

  • [Journal Article] Astrocytes as determinants of disease progression in inherited amyotrophiclateral sclerosis.2008

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

      Nat Neurosci. 11

      Pages: 251-253

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] L347P PINK1 mutant that fails to bind to Hsp90/cdc37 chaperones is rapidlydegraded in a proteasome-dependant manner.2008

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

      Neurosci. Res. (In press)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Rines/RNF180, a novel RING finger gene-encoded product, is a membrane-bound ubiquitin ligase.2008

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

      Gene Cells (In press)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Evolution of mitochondrial cell death pathway: Proapoptotic role of HtrA2/Omi in Drosophila.2007

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

      Biochem Biophys Res Commun. 356

      Pages: 993-997

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Heat-shock protein 105 interacts with and suppresses aggregation of mutant Cu/Zn superoxide dismutase; clues to a possible strategy for treating ALS.2007

    • Author(s)
      Yamashita, H., et. al.
    • Journal Title

      J. Neurochem. 102

      Pages: 1497-1505

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Rac-GAP a-Chimerin Regulates Motor-Circuit Formation as a Key Mediator of EphrinB3/EphA4 Forward Signaling.2007

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

      Cell 130

      Pages: 742-753

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pael receptor is involved dopamine metabolism in the nigrostriatalsystem.2007

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

      Neurosci. Res. 59

      Pages: 413-425

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Heterogeneous epileptogenicity and cortical function within malformations of cortical development : A case report.2007

    • Author(s)
      Kinoshita, M.
    • Journal Title

      J Neurol Sci 251(1-2)・1

      Pages: 129-133

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Presenilin 1 is involved in the maturation of beta-site amyloid precursor protein-cleaving enzyme1 (BACE1).2007

    • Author(s)
      Kuzuya, A.
    • Journal Title

      J Neurosci Res 85・1

      Pages: 153-165

    • 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, whichis enhanced under condition of parkin inactivation.2007

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

      Hum Mol Genet. 16・1

      Pages: 50-60

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Expression of S100 protein and protective effect of arundic acid on the at brain in chronic cerebral hypoperfusion.2007

    • Author(s)
      Ohtani, R.
    • Journal Title

      Brain Res 1135・1

      Pages: 195-200

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Accumulation of Hsc70 and Hsp70 in glial cytoplasmic inclusions in patients with multiple system atrophy.2007

    • Author(s)
      Kawamoto, Y.
    • Journal Title

      Brain Res 1136・1

      Pages: 219-227

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Localization of Id2 mRNA in the adult mouse brain.2006

    • Author(s)
      Kitajima, K.
    • Journal Title

      Brain Res 1073-1074

      Pages: 93-102

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Epileptic polyopia with right temporal lobe epilepsyas studied by FDG-PET and MRI : A case report.2006

    • Author(s)
      Mitsueda-Ono, T.
    • Journal Title

      J Neurol Sci 247・1

      Pages: 109-111

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Generators and temporal succession of giant somatosensory evoked potentials in cortical reflex myoclonus : Epicortical recording fromsensorimotor cortex.2006

    • Author(s)
      Hitomi, T.
    • Journal Title

      Clin Neurophysiol 117・7

      Pages: 1481-1486

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Structure of human ubiquitin-conjugating enzyme E2 G2 (UBE2G2/UBC7).2006

    • Author(s)
      Arai, R.
    • Journal Title

      Acta Crystallograph Sect F Struct Biol Cryst Commun 62・4

      Pages: 330-334

    • Related Report
      2006 Annual Research Report
  • [Journal Article] alpha-Synuclein is colocalized with 14-3-3 and synphilin-1 in A53T transgenic mice.2006

    • Author(s)
      Shirakashi, Y.
    • Journal Title

      Acta Neuropathol (Berl) 112・6

      Pages: 1456-1469

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Matrix metalloproteinase-2plays a critical role in thepathogenesis of white matter lesions after chronic cerebral hypoperfusion in rodents.2006

    • Author(s)
      Nakaji, K.
    • Journal Title

      Stroke 37・11

      Pages: 2816-2823

    • Related Report
      2006 Annual Research Report
  • [Journal Article] ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of Parkin.2006

    • Author(s)
      Omura, T.
    • Journal Title

      J Neurochem 99・6

      Pages: 1456-1469

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Heat-shock protein 105 interacts with and suppresses aggregation of mutant Cu/Zn superoxide dismutase; clues to a possible strategy for treating ALS.

    • Author(s)
      Yamashita, H.
    • Journal Title

      J Neurochem (in press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] PINK1, a gene product ofPARK6, accumulates in{alpha}-synucleinopathy brains.

    • Author(s)
      Murakami, T.
    • Journal Title

      J Neurol Neurosurg Psychiatry (in press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Cell type-specific upregulation of parkin in response to ER stress.

    • Author(s)
      Wang, H.
    • Journal Title

      ARS Forum (in press)

    • Related Report
      2006 Annual Research Report
  • [Presentation] 家族性パーキンソン病と小胞体ストレス。2007

    • Author(s)
      高橋良輔
    • Organizer
      BMB2007
    • Place of Presentation
      横浜
    • Year and Date
      2007-12-13
    • Related Report
      2007 Annual Research Report
  • [Presentation] The molecular mechanisms underlying parkin-related parkinsonism.2007

    • Author(s)
      Takahashi, R.
    • Organizer
      Croucher Advanced Study Institute-Innovative therapies of movement disorders; basic and clinical sciences-
    • Place of Presentation
      Hong Kong, China
    • Year and Date
      2007-11-28
    • Related Report
      2007 Annual Research Report
  • [Presentation] 家族性パーキンソン病を起こす原因蛋白は相互に作用しあうか?2007

    • Author(s)
      高橋良輔
    • Organizer
      第一回Movement Disorder Society, Japan学術集
    • Place of Presentation
      東京
    • Year and Date
      2007-10-05
    • Related Report
      2007 Annual Research Report
  • [Presentation] PAEL-R Transgenic mouse crossed with parkin deficient mouse displays persistent endoplasmic reticulum stress, reduction in mitochondrial complex I activity and selective dopaminergic neuronal death.2007

    • Author(s)
      Takahashi, R.
    • Organizer
      FASEB Summer Research Conferences
    • Place of Presentation
      Indian Wells, U.S.A.
    • Year and Date
      2007-07-31
    • Related Report
      2007 Annual Research Report
  • [Presentation] 家族性パーキンソン病の動物モデル。2007

    • Author(s)
      高橋良輔
    • Organizer
      第48回日本神経学会総会
    • Place of Presentation
      名古屋
    • Year and Date
      2007-05-17
    • Related Report
      2007 Annual Research Report
  • [Remarks]

    • URL

      http://www.kuhp.kyoto-u.ac.jp/~neurology/

    • Related Report
      2007 Annual Research Report

URL: 

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

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