2005 Fiscal Year Final Research Report Summary
The study of modulation of neuronal cell death and searching for new functional molecule regulated by endoplasmic reticulum stress and by innate immune system
| Project/Area Number |
16590040
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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 |
Biological pharmacy
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| Research Institution | CHIBA INSTITUTE OF SCIENCE (2005)
Hokkaido University (2004) |
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Principal Investigator |
OKUMA Yasunobu Chiba Institute of Science, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (20127939)
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| Co-Investigator(Kenkyū-buntansha) |
OKUMA Yasunobu Chiba Institute of Science, Faculty of Pharmaceutical Sciences, Professor (20127939)
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| Project Period (FY) |
2004 – 2005
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| Keywords | neuronal cell death / ER stress / innage immunity / chemical chaperon / 4-phenylbutylate |
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| Research Abstract |
Recent studies have shown that neurodegenerative disorders such as Alzheimer's and Parkinson's diseases are involved in a disruption of endoplasmic reticulum (ER) function. We investigated the effects of 4-phenylbutylate (4-PBA) on the accumulation of Parkin-associated endothelin receptor-like receptor (Pael-R) pathologically relevant to the loss of dopaminergic neurons in autosomal recessive juvenile Parkinsonism (AR-JP). 4-PBA restored the normal expression of Paer-R protein and suppressed ER stress induced by the accumulation of Paer-R. In addition, we showed that 4-PBA attenuated the activation of ER-stress-induced signal transduction pathways and subsequent neuronal cell death. Furthermore, we revealed that 4-PBA possesses chemical chaperon activity in vitro, which prevents the aggregation of denatured α-lactalbumin and bovine serum albumin (BSA).
Epidemiological evidence has shown that non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of Parkinson's disease and Alzheimer's disease. However, the mechanism (s) by which NSAIDs elicit their anti-neurodegenerative effects is not clear. We found that pretreatment with aspirin significantly inhibited tunicamycin-induced ER-stress response such as XBP-1 mRNA splicing and induction of GRP78 and CHOP. Furthermore, we demonstrated that aspinin directly inhibited the aggregation of reduced α-lactalbumin and BSA, indicating the possibility that aspirin act as a chemical chaperone.
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