| Project/Area Number |
13670637
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | Fujita Health University (2002-2003)
福井医科大学 (2001) |
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Principal Investigator |
MUTOH Tatsuro Fujita Health University, School of Medicine, Associate Professor, 医学部, 助教授 (60190857)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2003: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2002: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | rafts / Alzheimer's disease / glycosphingolipids / TrK / Ganglioside / cholesterol / PS1 / PI-3 Kinase / カベオラ / グルコシルセラミド / 神経成長因子 / γ-セクレターゼ / シグナル伝達 / チロシン燐酸化 / Caveola / Apoptosis / NGF / neuroblastoma / Raft / signal transduction / tyrosine phosporylation / apoptosis |
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| Research Abstract |
In many neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease, abnormal proteins such as Abeta peptides, hyperphosphrylated tau and synuclein are accumulated In the Intra-and extra-cellular spaces of the neurons. Some of them are due to the overload to ERAD system which Initiates the signal for cell death. In this study, we explored the significance of the membrane caveolae or lipid rafts to compete with such signals for cell death acting as a machinery for the protection of the cell death. For these purposes, we initiated to work on the molecular effect of GM1 ganglioside (GM1), main constituent of lipid rafts on the lipid rafts-resident Trk high affinity neurotrophic receptors. Then, we examined the effect of cholesterol depletion with HMG-CoA reductase inhibitor (HCRI) on the Integrity of lipid rafts and the fate of the muscle-derived cell culture system. Finally, we examined the effects of the mutation of presenilin-1 gene, a causative gene for familial Alzheimer's disease on glycosphingolipids biosynthesis and metabolism.
These analyses revealed following facts ; 1) Trk was no more reactive to its ligand when GM1 is depleted in the lipid rafts, wheras 2)stable transfection of GMI synthase gene rescued the responsiveness of the Trk protein to its ligand. In L myoblasts, 3)cellular cholesterol depletion with HCRI resulted in the apoptotic cell death provoking the tyrosine phosphorylation of p110 catalytic subunit of phosphatidylinositol-3 kinase. 4) In these conditions, we could no more detect lipid rafts fraction of these cells. In the final, we found that 5) mutation of PSi gene resulted in the prevention of cellular gangliosides and 6)an abnormal subcellular distribution of Trk neurotrophin receptor. These abnormal reduction of cellular gangliosides seemed to be an abnormal reduction of glucosylceramide in the cells.
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