Studies of neurodegenerative processes and alpha-synuclein expression focusing on regional specificity of astrocytes.
| Project/Area Number |
19K07993
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 52020:Neurology-related
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| Research Institution | Okayama University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
浅沼 幹人 岡山大学, 医歯薬学域, 教授 (00273970)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | パーキンソン病 / α-シヌクレイン / ロテノン / アストロサイト / ミクログリア / ドパミン神経障害 / ドパミン神経細胞 / 腸管神経系 / 神経科学 / 脳神経疾患 / 脳・神経 / グリア細胞 |
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| Outline of Research at the Start |
孤発性パーキンソン病(PD)におけるLewy小体を伴う神経障害機構は未だ解明されていない．Lewy小体の主要構成成分であるα-シヌクレイン(α-syn)の凝集・蓄積および伝播がPD発症の重要な要因として注目されている．本研究では，アストロサイトの部位特異性がもたらす神経細胞内α-syn動態と環境毒ロテノン誘発α-syn凝集体形成・選択的神経障害との連関について初代培養細胞およびロテノン投与PDモデルマウスを用いて検討し，PDにおける中枢および末梢神経系のLewy小体形成および神経障害機構の解明を目指す．
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| Outline of Final Research Achievements |
In this study, we revealed that mesencephalic astrocyte-microglia interaction promoted a pesticide rotenone-induced dopaminergic neurotoxicity. In addition, we demonstrated that mesencephalic astrocytes upregulated alpha-synuclein expression in the dopaminergic neurons. We examined secreted molecules from rotenone-treated mesencephalic astrocyte and microglia co-culture by LC-MS/MS analysis. It is demonstrated increase in the inflammatory molecules and decrease in the antioxidants and a protein which inhibits alpha-synuclein aggregation and cell-to-cell propagation. In rotenone-injected parkinsonian mice, we observed alpha-synuclein aggregation and neurodegeneration not only in the central nervous system but also peripheral enteric nervous system. However, change in the alpha-synuclein expression and neurodegeneration are not parallel in some brain region. These results suggest some factors in addition to alpha-synuclein aggregation are involved in region-specific neurodegeneration.
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| Academic Significance and Societal Importance of the Research Achievements |
近年，グリア細胞の部位特異性や神経-グリア連関が注目されつつある．本研究では，アストロサイトの部位特異性が神経細胞でのα-syn発現動態を規定すること，ロテノン誘発ドパミン神経障害においては部位特異的アストロサイト-ミクログリア相互連関が重要であることを明らかにした．また，孤発性パーキンソン病における特定の神経系におけるLewy小体を伴う神経障害機構を解明するためには，アストロサイト-ミクログリア相互連関の部位特異性に着目する必要性があることを提示した．また，本研究でのグリア細胞が部位特異的に分泌する神経障害性分子の同定結果は，今後の神経保護薬開発に寄与しうる．
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Report
(4 results)
Research Products
(47 results)
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[Presentation] Rotenone-induced dopaminergic neurotoxicity mediated by astrocyte-microglia interaction.2021
Author(s)
Miyazaki, I., Kikuoka, R., Isooka, N., Murakami, S., Sogawa, C., Sogawa, N, Kitamura, Y., Asanuma, M.
Organizer
第62回日本神経学会学術大会
Related Report
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[Presentation] Region-specific glial dysfunction promotes rotenone neurotoxicity.2020
Author(s)
Miyazaki, I., Kikuoka, R., Isooka, N., Sogawa, C., Sogawa, N, Kitamura, Y., Asanuma, M.
Organizer
第61回日本神経学会学術大会
Related Report
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[Presentation] Region-specific features of astrocytes against dopaminergic neurotoxin-induced oxidative stress.2019
Author(s)
Asanuma, M., Okumura-Torigoe, N., Miyazaki, I., Murakami, S., Kitamura, Y. and Sendo, T.
Organizer
14th European Meeting on Glial Cells in Health and Disease
Related Report
Int'l Joint Research
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[Presentation] Regional differences in reaction of astrocytes against rotenone contribute to dopaminergic neurodegeneration.2019
Author(s)
Miyazaki, I., Asanuma, M., Murakami, S., Kikuoka, R., Isooka, N., Sogawa, C., Sogawa, N. and Kitamura, Y.
Organizer
14th European Meeting on Glial Cells in Health and Disease
Related Report
Int'l Joint Research
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[Presentation] Involvement of region-specific glial dysfunction in rotenone neurotoxicity.2019
Author(s)
Miyazaki, I., Asanuma, M., Murakami, S., Kikuoka, R., Isooka, N., Sogawa, C., Sogawa, N. and Kitamura, Y.
Organizer
VI Asian College of Neuropsychopharmacology (AsCNP)
Related Report
Int'l Joint Research
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[Presentation] Rotigotine protects dopaminergic neurons via astrocytic serotonin 1A receptors.2019
Author(s)
Miyazaki, I., Isooka, N., Kikuoka, R., Wada, K., Nakayama, E., Shin, K., Yamamoto, D., Kitamura, Y., Asanuma, M.
Organizer
第60回日本神経学会学術大会
Related Report
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[Presentation] 妊娠・授乳期のエポキシ樹脂曝露が新生仔マウスに及ぼす行動毒性.2019
Author(s)
宮崎育子, 菊岡 亮, 磯岡奈未, 禅正和真, 新居 麗, 園部奏生, 船越英丸, 中山恵利香, 進 浩太郎, 山本大地, Kyle Quin, 浅沼幹人
Organizer
第46回日本毒性学会学術年会
Related Report
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