Schmidt Vanessa, Sporbert Anje, Rohe Michael, Reimer Tatjana, Rehm Armin, Andersen Olav M, Willnow Thomas E
Max-Delbrueck Center for Molecular Medicine, Robert-Roessle-Strasse 10, Berlin, Germany.
J Biol Chem. 2007 Nov 9;282(45):32956-64. doi: 10.1074/jbc.M705073200. Epub 2007 Sep 12.
SorLA has been recognized as a novel sorting receptor that regulates trafficking and processing of the amyloid precursor protein (APP) and that represents a significant risk factor for sporadic Alzheimer disease. Here, we investigated the cellular mechanisms that control intracellular trafficking of sorLA and their relevance for APP processing. We demonstrate that sorLA acts as a retention factor for APP in trans-Golgi compartments/trans-Golgi network, preventing release of the precursor into regular processing pathways. Proper localization and activity of sorLA are dependent on functional interaction with GGA and PACS-1, adaptor proteins involved in protein transport to and from the trans-Golgi network. Aberrant targeting of sorLA to the recycling compartment or the plasma membrane causes faulty APP trafficking and imbalance in non-amyloidogenic and amyloidogenic processing fates. Thus, our findings identified altered routing of sorLA as a major cellular mechanism contributing to abnormal APP processing and enhanced amyloid beta-peptide formation.
SorLA已被公认为一种新型分选受体，它调节淀粉样前体蛋白（APP）的运输和加工，并且是散发性阿尔茨海默病的一个重要风险因素。在此，我们研究了控制SorLA细胞内运输的细胞机制及其与APP加工的相关性。我们证明，SorLA在反式高尔基体区室/反式高尔基体网络中作为APP的保留因子，阻止前体释放到常规加工途径中。SorLA的正确定位和活性依赖于与GGA和PACS-1的功能性相互作用，GGA和PACS-1是参与往返反式高尔基体网络蛋白质运输的衔接蛋白。SorLA异常靶向回收区室或质膜会导致APP运输错误以及非淀粉样生成和淀粉样生成加工命运的失衡。因此，我们的研究结果确定SorLA的转运改变是导致APP加工异常和淀粉样β肽形成增加的主要细胞机制。
