TTC7 and Hyccin Regulate Neuronal Aβ42 Accumulation and its Associated Neural Deficits in Aβ42-Expressing Drosophila.
TTC7 and Hyccin Regulate Neuronal Aβ42 Accumulation and its Associated Neural Deficits in Aβ42-Expressing Drosophila.
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DOI：
10.3233/jad-170907
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发表时间：
2018-09
期刊：
影响因子：
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通讯作者：
Minghao Sun;Yinghui Zhao;Meng Han;Baozhu Zhang;Xiao Zhang;Qichao Zhang;N. Lim;Wen-An Wang;F. Huang
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文献类型：
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作者：
Minghao Sun;Yinghui Zhao;Meng Han;Baozhu Zhang;Xiao Zhang;Qichao Zhang;N. Lim;Wen-An Wang;F. Huang
神经元β淀粉样蛋白（Aβ）的蓄积在阿尔茨海默病（AD）的发病机制中起重要作用。Aβ的构象和毒性受质膜上脂质的调节。以前，我们发现在表达Aβ42的果蝇模型中，下调滚动阻断（RBO）或磷脂酰肌醇-4-激酶IIIα（PI 4KIII α）可减少神经元Aβ蓄积和相关的神经缺陷。在哺乳动物中，RBO和PI 4KIII α的同源物与支架蛋白TTC 7和胞质蛋白Hyccin/FAM 126 A形成质膜定位复合物，以严格控制磷脂酰肌醇-4-磷酸的质膜水平。在这里，我们发现果蝇TTC 7和Hyccin的遗传下调也减少了神经元Aβ积累和相关的突触和运动缺陷，以及Aβ42表达果蝇的过早死亡，而TTC 7和Hyccin的过表达产生了相反的效果。这些结果与我们先前的研究一起表明，RBO/TTC 7/PI 4KIII α/Hyccin调节果蝇模型中神经元Aβ积累和相关的神经缺陷，进一步支持RBO/Efr 3-PI 4KIII α复合物作为AD的潜在治疗靶点。
Neuronal amyloid-β (Aβ) accumulation plays an important role in the pathogenesis of Alzheimer's disease (AD). The conformation and toxicity of Aβ are regulated by lipids on the plasma membrane. Previously, we found downregulation of Rolling Blackout (RBO) or phosphatidylinositol-4-kinase type IIIα (PI4KIIIα) reduces neuronal Aβ accumulation and associated neural deficits in a Drosophila model expressing Aβ42. In mammals, the homologs of RBO and PI4KIIIα were reported to form a plasma membrane-localized complex with a scaffold protein TTC7 and cytosolic protein Hyccin/FAM126A to tightly control the plasmalemmal level of phosphatidylinositol-4-phosphate. Here, we show genetic downregulation of Drosophila TTC7 and Hyccin also reduces neuronal Aβ accumulation and associated synaptic and motor defects as well as premature death in Aβ42-expressing flies, while overexpression of TTC7 and Hyccin produced the opposite effect. These results, together with our previous study, demonstrate that RBO/TTC7/PI4KIIIα/Hyccin regulate neuronal Aβ accumulation and associated neural deficits in the Drosophila model, further supporting the RBO/Efr3-PI4KIIIα complex as a potential therapeutic target for AD.