Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signalling in Alzheimer's disease
Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signalling in Alzheimer's disease
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DOI：
10.1093/brain/awv356
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发表时间：
2016-02-01
期刊：
影响因子：
14.5
通讯作者：
Strittmatter, Stephen M.
中科院分区：
文献类型：
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作者：
Haas, Laura T.;Salazar, Santiago V.;Strittmatter, Stephen M.
小鼠中与阿尔茨海默病相关的表型可以通过阻断细胞朊病毒蛋白或代谢型谷氨酸受体 5 来挽救。我们寻找遗传和生化证据，证明这些蛋白质在大脑中作为专性复合物协同发挥作用。我们发现细胞朊病毒蛋白通过跨膜代谢型谷氨酸受体 5 与细胞内蛋白介质 Homer1b/c、钙/钙调蛋白依赖性蛋白激酶 II 和阿尔茨海默病风险基因产物蛋白酪氨酸激酶 2 beta 结合。细胞朊病毒蛋白与这些细胞内蛋白的偶联可通过可溶性β淀粉样蛋白寡聚体、小鼠脑阿尔茨海默病转基因或人类阿尔茨海默病病理学进行修饰。淀粉样蛋白-β寡聚体触发的细胞内蛋白质介质磷酸化和体外突触可塑性受损需要 Prnp-Grm5 遗传相互作用，在跨杂合子功能丧失中不存在，但在任一单一杂合子中都存在。重要的是，Prnp 和 Grm5 之间的遗传耦合还负责阿尔茨海默病转基因模型小鼠的信号传导、生存和突触损失。因此，代谢型谷氨酸受体5和细胞朊病毒蛋白之间的相互作用在阿尔茨海默病的发病机制中发挥着核心作用，并且该复合物是缓解疾病干预的潜在靶点。
Alzheimer's disease-related phenotypes in mice can be rescued by blockade of either cellular prion protein or metabotropic glutamate receptor 5. We sought genetic and biochemical evidence that these proteins function cooperatively as an obligate complex in the brain. We show that cellular prion protein associates via transmembrane metabotropic glutamate receptor 5 with the intracellular protein mediators Homer1b/c, calcium/calmodulin-dependent protein kinase II, and the Alzheimer's disease risk gene product protein tyrosine kinase 2 beta. Coupling of cellular prion protein to these intracellular proteins is modified by soluble amyloid-beta oligomers, by mouse brain Alzheimer's disease transgenes or by human Alzheimer's disease pathology. Amyloid-beta oligomer-triggered phosphorylation of intracellular protein mediators and impairment of synaptic plasticity in vitro requires Prnp-Grm5 genetic interaction, being absent in transheterozygous loss-of-function, but present in either single heterozygote. Importantly, genetic coupling between Prnp and Grm5 is also responsible for signalling, for survival and for synapse loss in Alzheimer's disease transgenic model mice. Thus, the interaction between metabotropic glutamate receptor 5 and cellular prion protein has a central role in Alzheimer's disease pathogenesis, and the complex is a potential target for disease-modifying intervention.