APP 与 GABA 受体形成复合物将轴突运输与淀粉样前体蛋白加工联系起来。
Complex formation of APP with GABA receptors links axonal trafficking to amyloidogenic processing.
机构信息
Department of Biomedicine, Institute of Physiology, University of Basel, Klingelbergstr. 50/70, 4056, Basel, Switzerland.
Faculty of Medicine, Institute of Physiology, University of Freiburg, Hermann-Herder-Str. 7, 79104, Freiburg, Germany.
出版信息
Nat Commun. 2019 Mar 22;10(1):1331. doi: 10.1038/s41467-019-09164-3.
GABA receptors (GBRs) are key regulators of synaptic release but little is known about trafficking mechanisms that control their presynaptic abundance. We now show that sequence-related epitopes in APP, AJAP-1 and PIANP bind with nanomolar affinities to the N-terminal sushi-domain of presynaptic GBRs. Of the three interacting proteins, selectively the genetic loss of APP impaired GBR-mediated presynaptic inhibition and axonal GBR expression. Proteomic and functional analyses revealed that APP associates with JIP and calsyntenin proteins that link the APP/GBR complex in cargo vesicles to the axonal trafficking motor. Complex formation with GBRs stabilizes APP at the cell surface and reduces proteolysis of APP to Aβ, a component of senile plaques in Alzheimer's disease patients. Thus, APP/GBR complex formation links presynaptic GBR trafficking to Aβ formation. Our findings support that dysfunctional axonal trafficking and reduced GBR expression in Alzheimer's disease increases Aβ formation.
GABA 受体（GBRs）是突触释放的关键调节因子，但对于控制其突触前丰度的运输机制知之甚少。我们现在表明，APP、AJAP-1 和 PIANP 中的序列相关表位以纳摩尔亲和力结合到突触前 GBR 的 N 端 sushi 结构域。在这三种相互作用的蛋白质中，选择性地遗传缺失 APP 会损害 GBR 介导的突触前抑制和轴突 GBR 表达。蛋白质组学和功能分析表明，APP 与 JIP 和钙黏蛋白蛋白相互作用，将 APP/GBR 复合物在货物囊泡中与轴突运输马达连接起来。与 GBR 形成复合物可稳定细胞表面的 APP，并减少 APP 向 Aβ 的蛋白水解，Aβ 是阿尔茨海默病患者老年斑的组成部分。因此，APP/GBR 复合物的形成将突触前 GBR 运输与 Aβ 形成联系起来。我们的研究结果支持这样一种观点，即阿尔茨海默病中功能失调的轴突运输和 GBR 表达减少会增加 Aβ 的形成。
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