Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein
Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein
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DOI：
10.1073/pnas.0503689102
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发表时间：
2005-09-20
影响因子：
11.1
通讯作者：
Willnow, TE
中科院分区：
文献类型：
--
作者：
Andersen, OM;Reiche, J;Willnow, TE
sorLA（分类蛋白相关受体）是一种功能未知的1型膜蛋白，在神经元中表达。它与在质膜、核内体和高尔基体之间穿梭的分选受体的同源性表明在神经元运输过程中具有相关功能。由于sorLA在阿尔茨海默病（AD）患者的大脑中表达减少，我们测试了该受体参与淀粉样蛋白前体蛋白（APP）到淀粉样蛋白β肽（A β）的细胞内运输和加工，A β是老年斑的主要成分。我们证明了sorLA在体外和活细胞中与APP相互作用，并且两种蛋白在内体和高尔基区室中共定位。sorLA在神经元中的过度表达导致APP重新分配到高尔基体，并减少对A β的加工，而在敲除小鼠中sorLA表达的减少导致大脑中A β水平升高，与AD患者的情况相似。因此，sorLA作为一种分选受体，保护APP不被加工成a β，从而减少淀粉样蛋白肽形成的负担。因此，人脑中受体表达的减少可能会增加A β的产生和斑块的形成，并促进自发性AD。
sorLA (sorting protein-related receptor) is a type-1 membrane protein of unknown function that is expressed in neurons. Its homology to sorting receptors that shuttle between the plasma membrane, endosomes, and the Golgi suggests a related function in neuronal trafficking processes. Because expression of sorLA is reduced in the brain of patients with Alzheimer's disease (AD), we tested involvement of this receptor in intracellular transport and processing of the amyloid precursor protein (APP) to the amyloid) beta-peptide (A beta), the principal component of senile plaques. We demonstrate that sorLA interacts with APP in vitro and in living cells and that both proteins colocalize in endosomal and Golgi compartments. Overexpression of sorLA in neurons causes redistribution of APP to the Golgi and decreased processing to A beta, whereas ablation of sorLA expression in knockout mice results in increased levels of A beta in the brain similar to the situation in AD patients. Thus, sorLA acts as a sorting receptor that protects APP from processing into A beta and thereby reduces the burden of amyloidogenic peptide formation. Consequently, reduced receptor expression in the human brain may increase A beta production and plaque formation and promote spontaneous AD.