2023 Fiscal Year Final Research Report
Elucidation of the mechanism of enteric neurodegeneration in environmental toxins-induced parkinsonism focusing on glial dysfunction
| Project/Area Number |
21K07415
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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) |
宮崎 育子 岡山大学, 医歯薬学域, 講師 (40335633)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Keywords | パーキンソン病 / 腸管先行性神経変性 / 腸管グリア細胞 / 環境毒ロテノン / 腸管細胞環境 / αシヌクレイン |
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| Outline of Final Research Achievements |
We investigated the pathology of gut-first neurodegeneration caused by exposure to rotenone, an environmental factor that causes Parkinson's disease (PD). In PD model mice chronically subcutaneously administered low-dose rotenone for 4 weeks, weakening of the intestinal mucosal barrier and specific accumulation of HMGB1 limited to the luminal cytoplasm of the mucosa were observed. Rotenone exposure to enteric nerve-glia cocultures caused the presence of M1/M2 macrophages and accumulation of α-synuclein, and addition of aggregated α-synuclein caused proliferation of M1 macrophages and retraction of neurites. These results suggest that abnormal accumulation of HMGB1 in the intestinal mucosa by exposure to environmental toxins causes impairment of autophagy and mucosal barrier function and inflammatory responses, and may lead to enteric glial dysfunction and neurodegeneration.
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| Free Research Field |
神経分子病態学，神経病態薬理学
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| Academic Significance and Societal Importance of the Research Achievements |
近年，パーキンソン病の疾患概念の変化に伴い，腸管先行性神経変性ならびに発症環境要因の存在に注目が集まりつつある．本研究では，環境要因の一つで孤発性パーキンソン病の脳腸の神経変性病態を再現できる低用量ロテノン慢性皮下投与PDモデルを用いて，環境毒曝露による腸管粘膜でのHMGB1の異常集積によるオートファジーの障害が，粘膜置換障害，粘膜バリアの破綻，炎症免疫反応といった細胞環境の変化をもたらし，これらが腸管グリア機能不全をもたらしている可能性を示すことができた．これは，腸管先行性神経変性の病態を明らかにし，それを抑制する神経保護薬開発に寄与する基礎資料となりうる．
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