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カテプシンD欠損が中枢神経細胞の機能に与える影響

组织蛋白酶 D 缺乏对中枢神经细胞功能的影响

基本信息

批准号：
12210101
负责人：
和栗聡
金额：
--
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至无数据
项目状态：
已结题

项目摘要

カテプシンD欠損マウスは生後2週から発育の遅滞が見られ、日齢26±1日で死に至る。同マウスでは日齢20日頃から痙攣が頻発するため、中枢神経系における形態学的解析に着手した。電子顕微鏡解析の結果、日齢20日以降の神経細胞体にオートファゴゾーム/リソゾーム様オルガネラ(細胞質の一部、オスミウム好性の顆粒状物質、フィンガープリント様構造物を含む)が蓄積し、また終末期にはミクログリアが細胞死に陥った神経細胞を取り囲んでいた。光学顕微鏡観察より神経細胞には自家蛍光物質の蓄積が認められ、さらに免疫組織学的解析において同構造物にはミトコンドリアのF1F0ATPaseのsubunit cが蓄積していた。以上の所見より、カテプシンD欠損マウスは神経性セロイドリポフスチノーシス(NCL)のモデルマウスとなり得ることが示唆された(Koike et al.,2000)。同マウス脳組織におけるリソゾーム/エンドゾーム系蛋白への影響を調べた結果、リソゾーム酵素のカテプシンBとtripeptidyl peptidase Iおよびリソゾーム膜蛋白として知られるlamp 1,lamp2の増加が認められた。一方リソゾーム酵素の輸送を担うマンノース6リン酸/IGF2受容体の増加は認められないことがら、本病態におけるカテプシンD以外のリソゾーム酵素の増加はリソゾーム酵素輸送系の亢進を伴わないものであることが示唆された。また、同マウスより得られる培養小脳顆粒細胞を光学顕微鏡レベルで解析した結果、神経突起のネットワーク形成に正常細胞との差は認められなかったが、カテプシンD欠損細胞には正常細胞には見られないsubunit c陽性顆粒およびlamp 1,lamp2強陽性のリング状構造物が認められた。このことは、NCL様の病態や加齢に伴うリソゾームの機能低下状態を解析する上で同培養細胞系を利用できることを示している。

2 weeks after birth and 26±1 days after death. At the same time, we began to analyze the morphology of central nervous system in 20 days. The results of electron microscope analysis showed that the concentration of cytosol/plasma (a part of cytoplasm, granular material, and other structural components) in the brain cells decreased by 20 days, and the concentration of cytosol/plasma was increased in the terminal stage. The accumulation of fluorescent substances in neurons was detected by optical microscopy, and the F1F0 ATPase subunit c was accumulated in the same structure. The above findings are based on the following observations: (1) The first is the analysis of the relationship between the brain and the brain;(2) The second is the analysis of the relationship between the brain and the brain;(3) The third is the analysis of the relationship between the brain and the brain;(4) The fourth is the analysis of the relationship between the brain and the brain;(5) The fourth is the analysis of the relationship between the brain and the brain;(6) The fourth is the analysis of the relationship between the brain and the brain;(7) The fourth is the analysis of the relationship between the brain and the brain;(8) The fourth is the analysis of the relationship between the brain and the brain;(9) The fourth is the analysis of the relationship between the brain and the brain;(8) The fourth is the analysis of the relationship between the brain and the brain;(9) The fourth is the analysis of the relationship between the brain and the brain. 2000)。The results showed that the expression of protein B and tripeptidyl peptidase I was significantly higher than that of lamp 1 and lamp2. The expression of protein B and tripeptidyl peptidase I was significantly higher than that of lamp2. The transport of a single enzyme is responsible for the increase in activity of 6-hydroxy-6-hydroxy-l/IGF2 receptors, and the increase in activity of a single enzyme other than the primary enzyme is responsible for the increase in activity of the enzyme transport system. The results of optical microscopy analysis of cultured granulosa cells showed that there was a difference between normal cells and normal cells in the formation of neurogenesis, and that there was a difference between normal cells and normal cells in the formation of neurogenesis. This is the first time that NCL has been used to analyze the dysfunctional state of NCL.