| Project/Area Number |
18500243
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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 |
Neuroscience in general
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| Research Institution | Okayama University |
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Principal Investigator |
TOMIZAWA Kazuhito Okayama University, Grad. Sch. of Med, Dent, and Phama. Sci, Associate Professor (40274287)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUI Hideki Okayama University, Grad. Sch. of Med, Dent, and Phama Sci, Professor (30157234)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥4,020,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥420,000)
Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | lipid transport / membrane transport / Cdk5 / cyclin / Niemann-Pick diseases / neurodegeneration / NPC1 / サイクリン依存性リン酸化酵素 |
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| Research Abstract |
Niemann-Pick type Cl (NPC1) disease is an autosomal-recessive cholesterol-storage disorder characterized by liver dysfunction, hepatosplenomegaly, and progressive neurodegeneration. At the cellular level, NPC1 disease is characterized by an accumulation of cholesterol within late endosomes/lysosomes derived from both endogenously synthesized cholesterol and endocytosis of lipoprotein-derived cholesterol through the coated-pit pathway. Mutations of NPC1 gene are found about 95 % in the patients with NPC1 disease. The mutations are observed both intracellular domain and the binding domain with lipid.
The aim of present study is to examine the effect of phosphorylation of the intracellular domain of NPC1 on abnormal intracellular cholesterol homeostasis in Niemann-Pick diseases. Mutant NPC1 seen in the patients with Niemann-Pick diseases was phosphorylated by cyclin-dependent Iciness 5 (Cdk5) in vitro. We identified the phosphorylation sites. Cdk5 phosphorylated NPC1 at Ser320. Phospho-specific antibody, which recognizes the Cdk5-dependent phosphorylation of NPC1 reveals that mutant NPC1 in the fibroblasts in patients with Niemann-Pick diseases is phosphorylated by Cdk5. Moreover, the phosphorylation was inhibited by Cdk5 inhibitors. In contrast, the phosphorylation was not detected in wild-type NPC1 expressing fibroblasts. Finally, the phosphorylation inhibited the change of NPC1 localization to mitochondria.
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