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MITOLはパーキンソン病原因遺伝子産物Parkinの分解を通して細胞保護的に働く

椎葉 一心 東京薬科大学

2022.03.18

概要

ミトコンドリア選択的オートファジーであるマイトファジーは、損傷したミトコンドリアを除去し細胞を傷害から保護する役割を果たしている。パーキンソン病原因遺伝子PINK1およびParkinはマイトファジーの主要因子であり、ミトコンドリアの膜電位低下に伴いPINK1が外膜上に凝集し、Parkinが細胞質から損傷ミトコンドリアに移行することでマイトファジーが実行される。これらの遺伝子変異はパーキンソン病における黒質線条体のドーパミン神経脱落に関連すると考えられている。これまでにParkinの機能や活性制御、ミトコンドリア移行機序に関して多くの解析が行われてきた。結果、病因変異を持つParkinは様々な機能欠失等を示すことが明らかとなったが、孤発性パーキンソン病患者が持つ野生型Parkinの量的動態について詳細な解析は行われていない。本研究グループではミトコンドリア外膜を4回膜貫通する膜型ユビキチンリガーゼMITOL/MARCH5を同定し、MITOLが基質をユビキチン化し分解することでミトコンドリアの機能・形態維持に貢献することを報告してきた。今回、私はマイトファジー誘導時においてMITOLがParkinを分解することを明らかとし、さらにマイトファジー後期においてMITOLが小胞体へ移行することも同時に発見した。この動的挙動は以前の報告にあるミトコンドリア抗アポトーシスタンパク質(FKBP38,Bcl-2)と類似していることから詳しい解析を行ったところ、MITOLはFKBP38依存的に小胞体へ移行することが観察された。また、小胞体移行後、MITOLは小胞体上で活性化型Parkinを分解し、FKBP38の量的減少を抑制することで過剰な細胞死を防いでいることを見出した。これらの結果より、MITOLはマイトファジーにおいて活性化型Parkinの量的調節を行い細胞に対し保護的な役割を果たしていることが示唆された。本研究成果は、MITOLの機能を制御しアポトーシスを調節することで老化に伴う神経細胞の変性(細胞死)を阻止するなど、孤発性パーキンソン病治療応用へとつながる可能性がある。

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