| Project/Area Number |
17500263
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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 | Nippon Medical School |
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Principal Investigator |
OHSAWA Ikuroh Nippon Medical School, Institute of Gerontology, Senior Assistant Professor (30343586)
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| Co-Investigator(Kenkyū-buntansha) |
KAMIMURA Naomi Nippon Medical School, Assistant Professor (60283800)
OHTA Shigeo Nippon Medical School, Graduate School of Medicine, Professor (00125832)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,670,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥270,000)
Fiscal Year 2007: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2006: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2005: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Keywords | Neuroscience / Differentiation / Mitochondria / Brain / Signal transduction |
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| Research Abstract |
Only a few human neuroblastoma cell-lines maintain the potential for neuronal differentiation. We noticed by chance that differentiable human neuroblastomas including SH-SY5Y have a specific mutation in the dihydrolipoamide-succinyltransferase (DLST) gene, whose product is a component of the α-ketoglutarate-dehydrogenase complex involved in mitochondrial energy metabolism. Here we demonstrate a requirement of energy-reduction for neuronal differentiation by restoring SH-SY5Y with the wild-type DLSTgene. Up-regulation of DLST activity increased mitochondrial membrane potential and impaired neuronal differentiation. The impairment was partially rescued by treatment with inhibitors of energy metabolism. Additionally, down-regulation of DLST expression with small interfering RNA enhanced neuronal differentiation in rat pheochromocytoma PC12 and primary cultured neocortical cells. We further found that mitochondrial membrane potential among SH-SY5Y cells was heterogeneous and lower in neuroblastic type cells. It is thus concluded that the casual mutation conferred the potential for differentiation on the neuroblastomas, suggesting that such mutants had been preferentially selected as a model cell-line for neuronal differentiation. The energy-reduction seemed to contribute to the differentiation by preventing cell-death. These results provide a new insight into neuronal differentiation.
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