| Project/Area Number |
18590355
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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 |
Human pathology
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| Research Institution | Tokyo Metropolitan Institute of Gerontology |
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Principal Investigator |
ISHIGAMI Akihito Tokyo Metropolitan Institute of Gerontology, Tokyo Metropolitan Foundation for Research on Aging and Promotion of Human Welfare, Senior research scientist (50270658)
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| Co-Investigator(Kenkyū-buntansha) |
HANDA Setsuko Tokyo Metropolitan Foundation for Research on Aging and Promotion of Human Welfare, 東京都老人総合研究所, Research Assistant (30360697)
久保 幸穂 (財)東京都高齢者研究・福祉振興財団, 東京都老人総合研究所, 助手 (00280769)
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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 |
¥3,900,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥300,000)
Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2006: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Keywords | Alzheimer's disease / neurodegenerative disorder / citrullinated protein / neuron / astrocyte / apoptosis / calcium / arginine |
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| Research Abstract |
Citrullinated proteins are the products of a post-translational process in which arginine residues undergo modification into citrulline residues when catalyzed by peptidylarginine deiminases (PADs) in a calcium ion-dependent manner Enzymatic citrullination abolishes positive charges of native protein molecules, inevitably causing significant alterations in their structure and functions. In mammalian tissues, PADs are found as five different isoforms (i.e, types 1-4, 6). PAD2 expressed mainly in the rat cerebrum became activated early in the neurodegenerative process. To elucidate the involvement of the citrullination in neuronal degeneration, we examined whether citrullinated proteins are produced in Alzheimer's disease (AD), Parkinson's disease, and Huntington chorea.
1. Histochemical analysis revealed that citrullinated proteins were detected all over the hippocampus. However, no citrullinated proteins were detected in the normal hippocampus. PAD2 immunoreactivity was also detected all over the hippocampus both in the AD and the normal brain. Double immunofluorescence staining revealed that citrullinated protein-and PAD2-positive cells were well coincidenced with GFAP-positive cells, but not all GFAP-positive cells were PAD2-positive cells. As GFAP is a astrocyte-specific marker protein, PAD2 is distributed mainly in astrocytes.
2. Citrullinated proteins with various molecular weight were detected in AD hippocampus by Western blot analysis, but not in normal brain. Two of the citrullinated proteins were identified as a vimentin and a glial fibrillary acidic protein (GFAP).
Thus, abnormal accumulation of citrullinated proteins and abnormal activation of PAD2 is occurring in AD hippocampus. These results strongly suggested that PAD has an important role in the onset and progression of AD and citrullinated proteins may became a possible useful marker for human neurodegenerative disease.
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