Tight control of the APP-Mint1 interaction in regulating amyloid production.
Tight control of the APP-Mint1 interaction in regulating amyloid production.
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严格控制 APP-Mint1 相互作用来调节淀粉样蛋白的产生。
DOI：
10.1016/j.brainres.2023.148496
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发表时间：
2023
期刊：
影响因子：
2.9
通讯作者：
Ho,Angela
中科院分区：
文献类型：
--
作者：
Henry,ShawnaM;Kistler,SabrinaA;Lagani,GavinD;Bartling,ChristianRO;Özcelik,Dennis;Sereikaite,Vita;Strømgaard,Kristian;Beffert,Uwe;Ho,Angela
淀粉样蛋白前体蛋白（APP）的蛋白水解过程产生淀粉样蛋白-β (a β)肽是阿尔茨海默病（AD）的一个致病事件。APP是一种跨膜蛋白，由YENPTY基序介导的APP内吞作用是a β生成的关键步骤。Mints是一类细胞质接头蛋白，直接结合APP的YENPTY基序，促进APP的转运和加工。在这里，我们生成并检测了两个Mint1突变体，Mint1的Tyr633Ala （Mint1Y633A）增强APP结合，以及Tyr549Ala和Phe610Ala突变体（Mint1Y549A/F610A）减少APP结合。我们研究了通过这些Mint1突变体干扰APP-Mint1相互作用如何改变APP和Mint1的细胞动力学以及Mint1与其他结合伙伴的相互作用。我们发现mint1y633特异性地增加了APP和早老素1 （γ分泌酶的催化亚基）的结合亲和力，从而增强了小鼠初级神经元的APP内吞作用。相反，Mint1Y549A/ f610a表现出APP亲和力降低和Aβ分泌减少。与敲除所有三种Mint蛋白相比，Mint1Y549A/ f610a1对a β释放的影响更大，支持APP-Mint1相互作用是a β产生的关键因素。总之，这项研究强调了靶向APP-Mint1相互作用作为AD治疗策略的潜力。
Generation of amyloid-β (Aβ) peptides through the proteolytic processing of the amyloid precursor protein (APP) is a pathogenic event in Alzheimer’s disease (AD). APP is a transmembrane protein and endocytosis of APP mediated by the YENPTY motif is a key step in Aβ generation. Mints, a family of cytosolic adaptor proteins, directly bind to the YENPTY motif of APP and facilitate APP trafficking and processing. Here, we generated and examined two Mint1 mutants, Tyr633Ala of Mint1 (Mint1Y633A) that enhanced APP binding, and Tyr549Ala and Phe610Ala mutant (Mint1Y549A/F610A), that reduced APP binding. We investigated how perturbing the APP-Mint1 interaction through these Mint1 mutants alter APP and Mint1 cellular dynamics and Mint1′s interaction with its other binding partners. We found that Mint1Y633Aincreased binding affinity specifically for APP and presenilin1 (catalytic subunit of γ-secretase), that subsequently enhanced APP endocytosis in primary murine neurons. Conversely, Mint1Y549A/F610Aexhibited reduced APP affinity and Aβ secretion. The effect of Mint1Y549A/F610Aon Aβ release was greater compared to knocking down all three Mint proteins supporting the APP-Mint1 interaction is a critical factor in Aβ production. Altogether, this study highlights the potential of targeting the APP-Mint1 interaction as a therapeutic strategy for AD.