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Abstract

Sorting-related receptor with A-type repeats (SORLA) is a sorting receptor for the amyloid precursor protein (APP) that prevents breakdown of APP into Aβ peptides, a hallmark of Alzheimer's disease (AD). Several cytosolic adaptors have been shown to interact with the cytoplasmic domain of SORLA, thereby controlling intracellular routing of SORLA/APP complexes in cell lines. However, the relevance of adaptor-mediated sorting of SORLA for amyloidogenic processes in vivo remained unexplored. We focused on the interaction of SORLA with phosphofurin acidic cluster sorting protein (PACS) 1, an adaptor that shuttles proteins between transGolgi network (TGN) and endosomes. Using PACS1 knockdown studies in neuronal cell lines and investigations in transgenic mice expressing a PACS1-binding defective mutant of SORLA, we document that disruption of SORLA and PACS1 interaction results in the inability of SORLA/APP complexes to sort to the TGN in neurons, and in increased APP processing in the brain. Loss of PACS1 also impairs proper expression of the cation-independent mannose-6 phosphate receptor and its target cathepsin B, a protease that breaks down Aβ. Thus, our data identified the importance of PACS1-dependent protein sorting for control of amyloidogenic burden via both SORLA-dependent and SORLA-independent mechanisms.