2007 Fiscal Year Final Research Report Summary
Endoplasmicreticulum(ER)stress and Parkinsonism
| Project/Area Number |
17500226
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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 |
Nerve anatomy/Neuropathology
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| Research Institution | Kanazawa University |
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Principal Investigator |
KITAO Yasuko Kanazawa University, Graduate School of Medical Science, Assistant Professor (00019613)
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| Co-Investigator(Kenkyū-buntansha) |
OGAWA Satoshi Kanazawa University, Graduate School of Medical Science, Professor (90283746)
HORI Osamu Kanazawa University, Graduate School of Medical Science, Associate Professor (60303947)
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| Project Period (FY) |
2005 – 2007
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| Keywords | Parkinson's disease / stress / endoplasmic reticulum / neuronal cell death |
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| Research Abstract |
Selective loss of dopaminergic neurons is the final common pathway in Parkinson's disease, the second most common neurodegenerative disorder. Selective neuronal expression of Pael-R(Parkin associated endothelin-like receptor)in mouse brain was achieved by injecting adenoviral vectors carrying a modified neuron-specific promoter and Cre-recombinase into the striatum. Upregulation of Pael-Receptor in the substantia nigra pars compacts (SNpc) of mice by retrograde infection induced endoplasmic reticulum(ER) stress lead to decreased levels of tyrosine hydroxylase and death of dopaminergic neurons. Neuronal cell death was not observed in the other areas of the brain projecting to/from the SNpc. The role of ER stress in dopaminergic neuronal vulnerability was highlighted by their decreased survival in mice deficient in the ubiquitin-protein ligase Parkin and the ER chaperone ORP150(150 kDa oxygen regulated protein), compared with their robust survival consequent to overexpression of either P
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arkin or an ER chaperone, 78 kDa glucose regulated protein (GRP78). Dopamine-related toxicity was also a key factor, as a dopamine synthetase inhibitor blocked neuronal death in parkin null mice. These data suggest a model in which ER- and dopamine-related slam are major contributors to decreased viability of dopaminergic neurons in a setting relevant to Parkinson's disease.
FENIB (familial encephalopathy with neuroserpin inclusion bodies)is caused by intracellular accumulation/polymerization of mutant neuroserpins. Transgenic rats overexpressing megsin (Tg meg), a newly identified serine protease inhibitor (serpin), demonstrated intraneuronal periodic-acid Schiff (PAS)-positive inclusions distributed throughout deeper layers of cerebral cortex, CA1 of the hippocampus, and substantia nigra. Hippocampal extracts from Tg meg rats showed increased expression of ER stress proteins, and activation of caspases-12 & -3, associated with decreased neuronal density. Enhanced ER stress was also observed in dopaminergic neurons in the substantia nigra, in parallel with decreased neuronal viability and motor coordination. In each case, PAS-positive inclusions were also positive for megsin. These data suggest that overexpression of megsin results in ER stress, eventuating in the formation of PAS-positive inclusions. Tg meg rats provide a novel model relevant to FENIB in which accumulation of serpins in the ER induces selective dysfunction/loss of specific neuronal populations. Less
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Research Products
(10 results)
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[Journal Article] Pael receptor induces death of dopaminergic neurons in the substantia nigra via endoplasmic reticulum stress and dopamine toxicity, which is enhanced under condition of parkin inactivation2007
Author(s)
Kitao, Y., Imai, Y., Ozawa, K., Kataoka, A., Ikeda, T., Soda, M., Namekawa, K., Kiyama, H., Stern, DM., Hori, O., Wakamatsu, K., Ito, S., Itohara, S., Takahashi, R., Ogawa, S
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Journal Title
Human Mol. Genetics 16(1)
Pages: 50-60
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Deletion of SERP1/RAMP4, a component of the endoplasmic reticulum(ER)translocation sites, leads to ER stress2006
Author(s)
Hori, O., Miyazaki, M., Tamatani, T., Ozawa, K., Takano, K., Okabe, M., Ikawa, M., Hartmann, M., Mai, P., Stern, M., Kitao, Y., Ogawa, S
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Journal Title
Mol. Cell. Biol 26
Pages: 4257-67
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] A rat model of human FENIB(familial encephalopathy with neuroserpin inclusion bodies)2006
Author(s)
Takano, K., Kitao, Y., Inagi, R., Momoi, T., Matsuyama, T., Miyata, T., Yoneda, Y., Iso, H., Stern, DM., Hon, O., Ogawa, S
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Journal Title
Biochem Biophys Res Commun 346
Pages: 1040-1047
Description
「研究成果報告書概要(欧文)」より
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