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SORLA-dependent and -independent functions for PACS1 in control of amyloidogenic processes

Item Type:Article
Title:SORLA-dependent and -independent functions for PACS1 in control of amyloidogenic processes
Creators Name:Burgert, T. and Schmidt, V. and Caglayan, S. and Lin, F. and Füchtbauer, A. and Füchtbauer, E.M. and Nykjaer, A. and Carlo, A.S. and Willnow, T.E.
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 A{beta} 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 A{beta}. Thus, our data identified the importance of PACS1-dependent protein sorting for control of amyloidogenic burden via both SORLA-dependent and SORLA-independent mechanisms.
Keywords:Amino Acid Sequence, Amyloid beta-Protein Precursor, Brain, Cathepsin B, Gene Knockdown Techniques, IGF Type 2 Receptor, LDL-Receptor Related Proteins, Membrane Transport Proteins, Molecular Sequence Data, Neurons, Protein Binding, Protein Interaction Domains and Motifs, Protein Transport, Tumor Cell Line, Vesicular Transport Proteins, Animals, Mice
Source:Molecular and Cellular Biology
Publisher:American Society for Microbiology
Page Range:4308-4320
Date:November 2013
Official Publication:https://doi.org/10.1128/MCB.00628-13
PubMed:View item in PubMed

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