2002 Fiscal Year Final Research Report Summary
Mechanism of degeneration of dopaminergic neurons in the midbrain
| Project/Area Number |
13670660
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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 | Kagoshima University |
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Principal Investigator |
IWATA Shin-ichi Kagoshima University, Faculty of Medicine, Research Associate, 医学部, 助手 (60253861)
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| Co-Investigator(Kenkyū-buntansha) |
NOMOTO Masahiro Ehime University, Faculty of Medicine, Professor, 医学部, 教授 (50208401)
SHIMIZU Takao Kagoshima University, Faculty of Medicine, Assistant Professor, 医学部, 講師 (10041336)
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| Project Period (FY) |
2001 – 2002
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| Keywords | Parkinson's disease / mouse / 6-hydroxydopamine / gene expression analysis / Gene tips / microarray / ATAC-PCR / apoptosis |
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| Research Abstract |
In order to clarify mechanisms underlying dopaminergic neuronal death in Parkinson's disease, a gene expression profiling study was performed in a rodent model of Parkinson's disease. In this model, mice are intrastriatally injected with 6-hydroxydopamine (6-OHDA), and dopaminergic neurons in the substantia nigra (SN) gradually die by retrograde degeneration. The SN were removed 2 hrs, 24 hrs, or 14 days after 6-OHDA administrations. Levels of mRNAs related to cell death or survival were quantified using adaptor-tagged competitive PCR (ATAC-PCR). The cyclin D1 gene showed an immediate increase in mRNA expression. After 24 hrs, when dopaminergic neurons were under intense degeneration, levels of caspase 8 mRNA and p53 apoptosis effecter related to pmp 22 (PERP) mRNA increased, and FAS mRNA conversely decreased. After 14 days, when the degeneration was attenuated, levels of PERP mRNA and serum- and glucocorticoid-regulated kinase (SGK) mRNA still increased. SGK has a similarity to AKT, which is an important molecule involved in nerve growth factor signal transduction. AKT mRNA levels are low in dopaminergic neurons. These results suggest that an increase in cyclin D1 mRNA triggers dopaminergic neurons to enter an abnormal cell cycle, which leads to neuronal degeneration and cell death, possibly induced by PERP and caspase 8. In addition to cell death-related genes, several survival-related genes are activated. SGK might function as a key enzyme for the survival of dopaminergic neurons.
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