遺伝的素因と環境因子の相互作用による神経細胞死

• 研究課題/領域番号: 09280103
• 研究種目: 特定領域研究(A)
• 配分区分: 補助金
• 研究機関: 順天堂大学
• 研究代表者: 水野 美邦 順天堂大学, 医学部, 教授 (30049043)
• 研究分担者: 直井 信 応用生化学研究所, 脳科学研究部門, 部長 (50022786) ; 太田 茂 広島大学, 医学部, 教授 (60160503) ; 清水 信義 慶應大学, 医学部, 教授 (50162706) ; 小澤 敬也 自治医科大学, 医学部, 教授 (30137707) ; 小川 紀雄 岡山大学, 医学部, 教授 (90033208) ; 柳原 武彦 大阪大学, 医学部, 教授 (70243201) ; 永津 郁子 藤田保健衛生大学, 医学部, 教授 (80084573)
• 研究期間 (年度): 1997 – 2000
• 研究課題ステータス: 完了 (2000年度)
• 配分額: 266,000千円 (直接経費: 266,000千円); 2000年度: 68,000千円 (直接経費: 68,000千円); 1999年度: 66,000千円 (直接経費: 66,000千円); 1998年度: 64,000千円 (直接経費: 64,000千円); 1997年度: 68,000千円 (直接経費: 68,000千円)
• キーワード: 神経細胞死 / パーキンソン病 / 家族性パーキンソン病 / 遺伝的素因 / 黒質神経毒 / 環境因子 / 遺伝子治療 / 神経栄耀因子

研究概要

常染色体性劣性遺伝の家族性パーキンソン病の原因蛋白であるParkinについて機能解析を推進し,これがユビキチンリガーゼの一種であることを明らかにした.Parkinの欠損により,これによりポリユビキチン化される蛋白が黒質に蓄積して黒質変性が進行すると推定できる.またParkinは,Golgi装置を経て軸索輸送小胞に結合し,シナプス小胞に運ばれ,その膜に存在することを明らかにした.今後alpha-synucleinとの関連や孤発型パーキンソン病におけるParkinの解析で,パーキンソン病の原因に関する研究の進展が期待できる.Parkin遺伝子については,その欠失変異の切断点が18タイプに分類されることを明らかにした.エキソン4欠失の切断点は日本人5家系,韓国人1家系に共通していた.更にFISHプローブを調製し,複合ヘテロ接合体の欠失変異のDNA診断を可能にした.
孤発型パーキンソン病に関しては,PD患者リンパ球で内在性神経毒N-methyl(R)-salsolinol生成律速酵素である中性N-methyltransferase活性が著しく高い例が存在することを明らかにした.本神経毒はアポトーシスを誘導して黒質神経細胞死を起こす.更にpropargylamine誘導体はこの細胞死機構に介入しアポトーシスを抑制して神経細胞保護活性を示すことを見い出した.またドパミン系作用薬が核内移行し,転写因子に直接作用している可能性を明らかにした.パーキンソン病の遺伝子治療に関しては,チロシン水酸化酵素,芳香族アミノ酸脱炭酸酵素,テトラヒドロビオプテリン合成の律速酵素GTPシクロヒドロラーゼIの各遺伝子を全て搭載したアデノ随伴ウイルスベクターをMPTP投与により作製したラットモデルで1年以上改善が継続することを明らかにし,サルを用いた前臨床研究でも効果を確認した.

研究成果

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