| Project/Area Number |
18500292
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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 |
Neurochemistry/Neuropharmacology
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
ENOKIDO Yasushi Tokyo Medical and Dental University, Med. Res. Inst., Assoc. Prof. (90263326)
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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 | Neuronal cell death / DNA-double strand break / Neuron / Astrocyte / Neurodegenerative disease / Aging / 酸化ストレス / 精神発達異常 / アポトーシス / ポリグルタミン病 / 神経幹細胞 / 精神発達遅延 |
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| Research Abstract |
Recent studies have shown that the defect of DNA repair/damage response mechanism in the nervous system closely associate with pathology underlying various neurodegenerative diseases. Accumulating results suggest that DNA damage may reduce transcriptional expression of genes involved in learning, memory and neuronal survival to initiate a program of brain ageing and pathogenesis. In this study, we focused on the molecular basis of DNA repair and damage responses underlying neurodegenerative diseases.
We performed a proteome analysis of soluble nuclear proteins prepared from neurons expressing mutant huntingtin exon 1 fragment protein which contains abnormally expanded poly-glutamine repeat (mHtt), and found that mHtt reduces the concentration of nuclear HMGB1 protein level. We also found that the reduction of nuclear HMGB1 causes DNA double-strand break (DDSB)-mediated neuronal damage in Huntinton's disease pathology. Using gene transgenic animals of mouse and fly that overexpressing DNA repair/damage response genes, we found that the improvement of DNA repair significantly recovers the symptoms of Huntinton's disease pathology. Furthermore, we investigated the regional and cell-type specific changes of HMGB1 and DDSB accumulation during the aging of mouse brain. HMGB1 is localized in the nuclei of neurons and astrocytes, and the protein level changes in various brain regions age-dependently. HMGB1 reduces in neurons, whereas it increases in astrocytes during aging. In contrast, DDSB remarkably accumulates in neurons, but it does not change significantly in astrocytes during aging. These results indicate that HMGB1 expression is differentially regulated between neuron and astrocyte, and suggest that the reduction of nuclear HMGB1 might be associated with DDSB-mediated neuronal dysfunction in the aging brain.
Our findings might provide us an effective strategy for developing new therapeutics against various neurodegenerative disorders.
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