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SORLA-Dependent and -Independent Functions for PACS1 in Control of Amyloidogenic Processes

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  • Tilman Burgert, Max Delbrueck Center for Molecular Medicine, Berlin, Germany, Germany
  • Vanessa Schmidt, Max Delbrueck Center for Molecular Medicine, Berlin, Germany, Germany
  • Safak Caglayan, Max Delbrueck Center for Molecular Medicine, Berlin, Germany
  • ,
  • Fuyu Lin, Denmark
  • Annette Füchtbauer
  • Ernst-Martin Füchtbauer
  • Anders Nykjaer
  • Anne-Sophie Carlo, Max Delbrueck Center for Molecular Medicine, Berlin, Germany
  • ,
  • Thomas E Willnow, Max Delbrueck Center for Molecular Medicine, Berlin, Germany
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 1 (PACS1), an adaptor that shuttles proteins between the trans-Golgi network (TGN) and endosomes. By studying PACS1 knockdown in neuronal cell lines and investigating transgenic mice expressing a PACS1-binding-defective mutant form of SORLA, we found 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 the 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 amyloidogenic-burden control via both SORLA-dependent and SORLA-independent mechanisms.
Original languageEnglish
JournalMolecular and Cellular Biology
Volume33
Issue21
Pages (from-to)4308-4320
Number of pages13
ISSN0270-7306
DOIs
Publication statusPublished - 3 Sep 2013

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