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KAKEN_23591254seika.pdf
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Title |
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新規病態スペクトラムALS/FTLD-Uにおける分子病態の解明
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シンキ ビョウタイ スペクトラム ALS/FTLD-U ニ オケル ブンシ ビョウタイ ノ カイメイ
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Shinki byotai supekutoramu ALS/FTLD-U ni okeru bunshi byotai no kaimei
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Novel pathological pathway of ALS/FTLD-U
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伊東, 大介
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イトウ, ダイスケ
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Ito, Daisuke
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慶應義塾大学・医学部・講師
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Research team head
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科研費研究者番号 : 80286450
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2014
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科学研究費補助金研究成果報告書
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2013
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筋萎縮性側策硬化症の原因遺伝子optineurin (OPNL)、ubiquilin (UBQLN)2が次々と同定されたが、その分子メカニズムは不明である. OPNLとUBQLN2はいずれも蛋白分解機構に関与することが知られており、我々の研究成果では、両分子がRab11陽性endosomal vesicleに共局在し、OPNLとUBQLN2のALS関連変異は、いずれもこのvesicleに障害を引き起こすことを観察している. さらに、このvesicleは、p62、ULK1陽性でありendosomeとautophagy をつなぐ蛋白品質管理に関連した新規の細胞内メカニズムである可能性が示唆された.
Ubiquilin (UBQLN) 2 localized in endosomal vesicles formed by the ALS-linked molecule optineurin (OPTN) and also co-localized with an initiator of the autophagic process, ULK1, after amino acid starvation. OPTN-vesicles were ubiquitin- and p62-immunopositive. An ALS-linked mutation (E478G) in OPTN abolished vesicle formation. ALS-linked mutations in UBQLN2 additively enhanced UBQLN2 aggregation and formation of inclusion bodies, resulting in mislocation from OPTN-vesicles. UBQLN2 was found to be a potent regulator of the levels of OPTN and the FTD-linked secretory factor progranulin, possibly via the endosomal system, and ALS-linked mutations disturbed these functional consequences. This study demonstrates that ALS-linked mutations in both OPTN and UBQLN2 interfere with the constitution of specific endosomal vesicles, suggesting that the vesicles are involved in protein homeostasis and that these proteins function in common pathological processes.
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研究種目 : 基盤研究(C)
研究期間 : 2011~2013
課題番号 : 23591254
研究分野 : 医歯薬学
科研費の分科・細目 : 内科系臨床医学・神経内科学
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