title: SorCS1 variants and amyloid precursor protein (APP) are co-transported in neurons but only SorCS1c modulates anterograde APP transport.
abstract: Processing of amyloid precursor protein (APP) into amyloid-β peptide (Aβ) is crucial for the development of Alzheimer's disease (AD). Because this processing is highly dependent on its intracellular itinerary, altered subcellular targeting of APP is thought to directly affect the degree to which Aβ is generated. The sorting receptor SorCS1 has been genetically linked to AD, but the underlying molecular mechanisms are poorly understood. We analyze two SorCS1 variants; one, SorCS1c, conveys internalization of surface-bound ligands whereas the other, SorCS1b, does not. In agreement with previous studies, we demonstrate co-immunoprecipitation and co-localization of both SorCS1 variants with APP. Our results suggest that SorCS1c and APP are internalized independently, although they mostly share a common post-endocytic pathway. We introduce functional Venus-tagged constructs to study SorCS1b and SorCS1c in living cells. Both variants are transported by fast anterograde axonal transport machinery and about 30% of anterograde APP-positive transport vesicles contain SorCS1. Co-expression of SorCS1b caused no change of APP transport kinetics, but SorCS1c reduced the anterograde transport rate of APP and increased the number of APP-positive stationary vesicles. These data suggest that SorCS1 and APP share trafficking pathways and that SorCS1c can retain APP from insertion into anterograde transport vesicles. Altered APP trafficking is thought to modulate its processing. SorCS1 has been suggested to function in APP trafficking. We analyzed if the two SorCS1 variants, SorCS1b and SorCS1c, tie APP to the cell surface or modify its internalization and intracellular targeting. We observed co-localization and vesicular co-transport of APP and SorCS1, but independent internalization and sorting through a common post-endocytic pathway. Co-expression of one variant, SorCS1c, reduced anterograde APP transport. These data demonstrate that SorCS1 and APP share trafficking pathways and that SorCS1c can retain APP from insertion into anterograde transport vesicles.
authors.affiliation: Institute for Molecular and Cellular Cognition, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Hermey
authors.affiliation: Division of Human Biology and Human Genetics, University of Kaiserslautern, Kaiserslautern, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Schmidt
authors.affiliation: Institute for Molecular and Cellular Cognition, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Bluhm
authors.affiliation: Institute for Molecular and Cellular Cognition, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mensching
authors.affiliation: Division of Human Biology and Human Genetics, University of Kaiserslautern, Kaiserslautern, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Ostermann
authors.affiliation: Division of Human Biology and Human Genetics, University of Kaiserslautern, Kaiserslautern, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Rupp
authors.affiliation: Institute for Molecular and Cellular Cognition, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Kuhl
authors.affiliation: Division of Human Biology and Human Genetics, University of Kaiserslautern, Kaiserslautern, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kins
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D027981:Symporters / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011956:Receptors, Cell Surface; C000595029:SORCS1 protein, mouse; D027981:Symporters
keywords: APP; Alzheimer's disease; SorCS1; Vps10p-Domain receptor; internalization; intracellular transport