単一遺伝子異常による神経細胞死

• Project/Area Number: 09280105
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas (A)
• Allocation Type: Single-year Grants
• Research Institution: Tokai University
• Principal Investigator: 池田 穣衛 (池田 穰衛) 東海大学, 総合医学研究所, 教授 (50266467)
• Co-Investigator(Kenkyū-buntansha): 辻 省次 新潟大学, 脳研究所, 教授 (70150612) ; 永津 俊治 藤田保健衛生大学, 総合医科学研究所, 教授 (40064802) ; 金澤 一郎 東京大学, 大学院・医学研究科, 教授 (30110498) ; 佐々木 秀直 北海道大学, 大学院・医学研究科, 講師 (80281806) ; 垣塚 彰 大阪バイオサイエンス研究所, 第4研究部, 部長(研究職) (80204329) ; 黒沢 良和 藤田保健衛生大学, 総合医科学研究所, 教授 (10109259)
• Project Period (FY): 2000
• Project Status: Completed (Fiscal Year 2000)
• Budget Amount: ¥240,000,000 (Direct Cost: ¥240,000,000); Fiscal Year 2000: ¥60,000,000 (Direct Cost: ¥60,000,000); Fiscal Year 1999: ¥56,000,000 (Direct Cost: ¥56,000,000); Fiscal Year 1998: ¥60,000,000 (Direct Cost: ¥60,000,000); Fiscal Year 1997: ¥64,000,000 (Direct Cost: ¥64,000,000)
• Keywords: 神経細胞死 / ポリグルタミン病 / アポトーシス / NAIP / トリブレットリピートインスタビリティー / ハンチントン病 / MJD / DRPLA / ポリグルタミン酸 / トリプレットリピートインスタビリティー / ダイナミックミューテーション / 神経変性疾患 / トリプレットリピート病 / 小脳変性疾患 / 脊髄性筋萎縮症 / マシャドジュセフ病 / 分子医学 / 歯状核赤核淡蒼球ルイ体萎縮症

Research Abstract

各神経変性疾患の平成12年度の成果は以下のように要約される。
【脊髄性筋萎縮症】NAIPの細胞特異的な発現にかかわる調節因子を同定した。NAIPの抗アポトーシス活性は酸化ストレス(ONOO)に特異的で、活性化にはストレス特異的に誘導されるプロテアーゼによるプロセッシングが必要であることが明らかになった(池田)。【ハンチントン病】病変型CAGリピートを有するハンチントン病遺伝子exon1の核内凝集体を精製し、構成成分としてヒストンコアタンパク質、hnRNP/HFにユビキチンが含まれていることを明らかにした(金澤)。病変型HD遺伝子(77CAG)ノックインマウスは、小脳を除いた脳組織全体でCAGリピートが伸長化して、組織全体でモザイク化していた。この現象は、線条体等で早期から観察され、週齢依存的に伸長化した。老齢マウスでは核内封入体が観察される等、ヒトHD患者との高い類似性が観察された(永津)。In vitro系を用いてCAGリピートの伸長複製を試みたが、異常複製は極めて低い頻度で起こりCAG特異的な増幅複製を再現することはできなかった。(黒沢)。内因性病変型HDトランスジェニックミニブタF1固体、2系統(雄1、雌1;現在3ヶ月齢、)が得られた。死産、若年死亡した3系統のF1固体について解析中(池田)。【歯状核赤核淡蒼球ルイ体萎縮症】伸長ポリグルタミン鎖とTAF130(TATA-bindingprotein-associated factor)が結合すること、この結合がcAMP-reponsive element-binding protein(CREB)-依存性の転写活性を強く抑制することを見いだした(辻)。【マシャド・ジョセフ病】MJDタンパク質の伸長ポリグルタミン特異的に結合する因子polyglutamine interacting protein 1:PIP1を精製・同定した。この分子の変異体は発現培養細胞において空胞形成と細胞死を引き起こす(垣塚)。MJD蛋白質はポリグルタミンの伸長の有無に関わらず、ゴルジ装置に凝集(coiled-coil領域が関与)した場合に強い細胞障害を起こす(西澤)。【優性遺伝性脊髄小脳変性症】新規の優性遺伝性運動失調症(1家系)SCA14遺伝子座、19q13.4を決定した(佐々木)。

Research Products

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