| Project/Area Number |
17590326
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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 Foundation for Research on Aging and Promotion of Human Welfare |
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Principal Investigator |
KUBO Sachiho Tokyo Metropolitan Foundation for Research on Aging and Promotion of Human Welfare, Tokyo Metropolitan Institute of Gerontology, Research assistant, 東京都老人総合研究所, 助手 (00280769)
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| Co-Investigator(Kenkyū-buntansha) |
MARUYAMA Naoki Tokyo Metropolitan Foundation for Research on Aging and Promotion of Human Welfare, Tokyo Metropolitan Institute of Gerontology, Vice director, 東京都老人総合研究所, 副所長 (00115940)
ISHIGAMI Akihito Tokyo Metropolitan Foundation for Research on Aging and Promotion of Human Welfare, Tokyo Metropolitan Institute of Gerontology, Research scientist, 東京都老人総合研究所, 主任研究員 (50270658)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2005: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Keywords | neurodegenerative disorder / Alzheimer's disease / arginine / citrullinated protein / neuron / astrocyte / aging / glial cell / ペプジルアルギニンデイミナーゼ |
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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. In our previous report, PAD2 expressed mainly in the rat cerebrum became activated early in the neurodegenerative process. To elucidate the involvement of protein citrullination in human neuronal degeneration, we examined whether citrullinated proteins are produced during Alzheimer's disease (AD). By Western blot analysis using anti-modified citrulline antibody, citrullinated proteins of varied molecular weights were detected in hippocampal tissues from patients with AD but not normal humans. Two of the citrullinated proteins were identified as vimentin and glial fibrillary acidic protein (GFAP) by using two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry. Interestingly, PAD2 was detected in hippocampal extracts from AD and normal brains, bu
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t the amount of PAD2 in the AD tissue was markedly greater. Histochemical analysis revealed citrullinated proteins throughout the hippocampus, especially in the dentate gyrus and stratum radiatum of CA1 and CA2 areas. However, no citrullinated proteins were detected in the normal hippocampus. PAD2 immunoreactivity was also ubiquitous throughout both the AD and normal hippocampal areas. PAD2-enrichment coincided well with citrullinated protein-positivity. Double immunofluorescence staining revealed that citrullinated protein- and PAD2-positive cells also coincided with GFAP-positive cells, but not all GFAP-positive cells were positive for PAD2. Like GFAP, which is an astrocyte-specific marker protein, PAD2 is distributed mainly in astrocytes. These collective results, the abnormal accumulation of citrullinated proteins and abnormal activation of PAD2 in hippocampi of patients with AD, strongly suggest that PAD has an important role in the onset and progression of AD and that citrullinated proteins may became a useful marker for human neurodegenerative diseases. Less
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