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

Abstract

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。

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.