2011 Fiscal Year Final Research Report
A novel signaling pathway that regulates brain aging
| Project/Area Number |
21300144
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | 財団法人東京都医学総合研究所 (2011)
Tokyo Metropolitan Organization for Medical Research (2009-2010) |
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Principal Investigator |
SAITOE Minoru 財団法人東京都医学総合研究所, 運動・感覚システム研究分野, 参事研究員 (50261839)
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| Project Period (FY) |
2009 – 2011
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| Keywords | 老化 / 学習記憶 / 遺伝子 / ショウジョウバエ / プロテオミクス |
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| Research Abstract |
Age-related memory impairment(AMI) is a debilitating consequence of brain aging that can be suppressed in Drosophila by reducing PKA activity. However, the molecular mechanisms underlying AMI remain unclear. Using proteome analyses of wild-type and PKA mutants, we identified an AMI-associated increase in the activity of Drosophila pyruvate carboxylase(dPC), a mitochondrial anaplerotic enzyme. Genetic and biochemical data demonstrate that age-related increases in glial dPC cause AMI and that PKA mutations suppress AMI by reducing dPC activity. Although increased oxidative stress has been proposed to cause AMI, increases in dPC activity are not associated with increased oxidative stress. Strikingly, although the production of D-serine, a glia-derived NMDA receptor agonist, decreases in aged flies, this decrease is suppressed by dPC mutations and AMI is ameliorated by feeding flies D-serine. We propose a novel oxidative stress-independent AMI signaling pathway in which age-related increases in glial mitochondrial dPC activity cause AMI by reducing D-serine production.
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