囊泡型 ATPase V0d1 次單元蛋白調節γ-Secretase 分 解類澱粉前驅蛋白與Notch 蛋白之反應

The Differential Modulation of γ-Secretase-mediated Cleavages of Amyloid Precursor Protein and Notch by the Vacuolar ATPase V0d1 Subunit

童永豪(Yung-Hao Tung)

指導教授 ： 廖永豐

共同指導教授 ： 潘建源

國立臺灣大學/生命科學院/動物學研究所/碩士(2014年)

https://doi.org/10.6342/NTU.2014.02738

摘要

阿茲海默症為全世界 65 歲以上老人失智症的主要原因，不斷增加的研究證據
指出了病人腦中，γ-seacretase 調控amyloid-β 的製造與此疾病之間有緊密關係，因
此一種治療或減緩病程的策略乃降低γ-seacretase 製造amyloid-β 之活性。近期研
究已發現了數個與γ-seacretase 具交互作用之蛋白質，具有調控γ-seacretase 活性之
能力。本實驗室先前的RNAi 篩選發現，囊泡型ATPase V0 的d1 次單元(ATP6V0d1)
為γ-seacretase 可能之調控者，為進一步明瞭此蛋白對γ-seacretase活性調控之角色，
因此在表現ATP6V0d1 之情況下，分別檢驗γ-seacretase 所催化之amyloid precursor
protein (APP-C99)與Notch (NΔE)蛋白水解的反應。實驗結果結果顯示了表現
ATP6V0d1 對於γ-seacretase 所調控之NΔE 之水解具有顯著之增強現象，同時降低
了細胞內APP-C99 之表現量，此一發現顯示了ATP6V0d1 可能選擇性的影響了
γ-seacretase 與其受質的作用。

關鍵字

阿茲海默症 ； γ-seacretase ； 類澱粉前驅蛋白 ； Notch 路徑 ； 囊泡型ATPase ； 溶小體 ； ATP6V0d1

並列摘要

Alzheimer’s disease (AD) is one of the major causes of dementia among people over
age of 65 around the world. Accumulated studies have shown a significant correlation
between the AD pathogenesis and the γ-seacretase-mediated (Aβ) production in the
patient’s brain. One of the possible strategies to cure or slow the disease progression of
AD is to reduce γ-seacretase activity to lower Aβ production. Resent reports have found
a number of γ-seacretase-interacting proteins that could potentially play a role in the
modulation of γ-seacretase activity. Our RNAi screen identified one of the
γ-seacretase-interacting proteins, vacuolar ATPase V0 domain d1 subunit (ATP6V0d1)
as a possible γ-seacretase modulator. To validate its role in the modulation of
γ-seacretase activity, γ-seacretase-catalyzed cleavages of amyloid precursor protein
(APP-C99) and Notch (NΔE) were examined in response to the overexpression of
ATP6V0d1. Our result demonstrated that overexpression of ATP6V0d1 does
significantly enhance the γ-secretase-mediated cleavage of NΔE, and also markedly
reduce the APP-C99 level. These findings suggest that ATP6V0d1 could act as a
modulator by differentially governing the interactions between γ-secretase and its
selective substrates.

並列關鍵字

Alzheimer’s disease ； γ-seacretase ； APP ； Notch pathway ； vacuolar ATPase ； lysosome ； ATP6V0d1

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