title: SORLA-dependent and -independent functions for PACS1 in control of amyloidogenic processes.
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 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.
authors.affiliation: Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Burgert
authors.forename: Vanessa
authors.initials: V
authors.lastname: Schmidt
authors.forename: Safak
authors.initials: S
authors.lastname: Caglayan
authors.forename: Fuyu
authors.initials: F
authors.lastname: Lin
authors.forename: Annette
authors.initials: A
authors.lastname: Füchtbauer
authors.forename: Ernst-Martin
authors.initials: EM
authors.lastname: Füchtbauer
authors.forename: Anders
authors.initials: A
authors.lastname: Nykjaer
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Carlo
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Willnow
mesh_terms: D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology; D002401:Cathepsin B / Q000096:biosynthesis; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000737:chemistry / Q000502:physiology*; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; C491914:PACS1 protein, human; D017527:Receptor, IGF Type 2; C102582:SORL1 protein, human; D033921:Vesicular Transport Proteins; C533912:CTSB protein, human; D002401:Cathepsin B