Retromer Binds the FANSHY Sorting Motif in SorLA to Regulate Amyloid Precursor Protein Sorting and Processing
Retromer Binds the FANSHY Sorting Motif in SorLA to Regulate Amyloid Precursor Protein Sorting and Processing
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DOI：
10.1523/jneurosci.2272-11.2012
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发表时间：
2012-01-25
影响因子：
5.3
通讯作者：
Andersen, Olav M.
中科院分区：
文献类型：
--
作者：
Fjorback, Anja W.;Seaman, Matthew;Andersen, Olav M.
SorLA是与阿尔茨海默病(AD)遗传相关的淀粉样前体蛋白(APP)的分选受体。逆转聚体是内小体到高尔基体恢复途径中的一个接头复合体，它与APP的运输有关，因为逆转聚体缺陷导致APP的分类和加工异常，并且在AD中逆转聚体蛋白的水平发生改变。在这里，我们报告了SorLA和Retmer在神经元中的功能相互作用，以控制APP的运输和淀粉样蛋白的形成过程。我们已经在SorLA的细胞质结构域中发现了一个序列(FANSHY)，该序列由逆转录复合体的VPS26亚基识别。因此，我们表征了逆转聚体复合体与SorLA之间的相互作用，并确定了逆转聚体在依赖SorLA的APP分类和加工中的作用。VPS26结合位点的突变导致受体重新分布到内体网络，类似于VPS26基因敲除细胞的情况。SorLA突变体保留了APP结合活性，但与野生型受体相反，APP被错误地引导到一个不同的非高尔基体内，导致淀粉样蛋白加工增加。综上所述，我们的数据提供了在散发性AD患者中发现的逆转聚体表达减少和淀粉样蛋白生成增加之间的分子联系。
sorLA is a sorting receptor for amyloid precursor protein (APP) genetically linked to Alzheimer's disease (AD). Retromer, an adaptor complex in the endosome-to-Golgi retrieval pathway, has been implicated in APP transport because retromer deficiency leads to aberrant APP sorting and processing and levels of retromer proteins are altered in AD. Here we report that sorLA and retromer functionally interact in neurons to control trafficking and amyloidogenic processing of APP. We have identified a sequence (FANSHY) in the cytoplasmic domain of sorLA that is recognized by the VPS26 subunit of the retromer complex. Accordingly, we characterized the interaction between the retromer complex and sorLA and determined the role of retromer on sorLA-dependent sorting and processing of APP. Mutations in the VPS26 binding site resulted in receptor redistribution to the endosomal network, similar to the situation seen in cells with VPS26 knockdown. The sorLA mutant retained APP-binding activity but, as opposed to the wild-type receptor, misdirected APP into a distinct non-Golgi compartment, resulting in increased amyloid processing. In conclusion, our data provide a molecular link between reduced retromer expression and increased amyloidogenesis as seen in patients with sporadic AD.