title: Protein sorting motifs in the cytoplasmic tail of SorCS1 control generation of Alzheimer's amyloid-β peptide.
abstract: Endosomal sorting of the Alzheimer amyloid precursor protein (APP) plays a key role in the biogenesis of the amyloid-β (Aβ) peptide. Genetic lesions underlying Alzheimer's disease (AD) can act by interfering with this physiological process. Specifically, proteins involved in trafficking between endosomal compartments and the trans-Golgi network (TGN) [including the retromer complex (Vps35, Vps26) and its putative receptors (sortilin, SorL1, SorCS1)] have been implicated in the molecular pathology of late-onset AD. Previously, we demonstrated a role for SorCS1 in APP metabolism and Aβ production and, while we implicated a role for the retromer in this regulation, the underlying mechanism remained poorly understood. Here, we provide evidence for a motif within the SorCS1c cytoplasmic tail that, when manipulated, results in perturbed sorting of APP and/or its fragments to endosomal compartments, decreased retrograde TGN trafficking, and increased Aβ production in H4 neuroglioma cells. These perturbations apparently do not involve turnover of the cell surface APP pool, but rather they involve intracellular APP and/or its fragments, downstream of APP endocytosis.
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Lane
authors.forename: John W
authors.initials: JW
authors.lastname: Steele
authors.forename: Dongming
authors.initials: D
authors.lastname: Cai
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Ehrlich
authors.forename: Alan D
authors.initials: AD
authors.lastname: Attie
authors.forename: Sam
authors.initials: S
authors.lastname: Gandy
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D019921:Biotinylation; D045744:Cell Line, Tumor; D003513:Cycloheximide / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D005910:Glioma / Q000473:pathology; D006801:Humans; D047468:Immunoprecipitation; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed / Q000379:methods; D009154:Mutation / Q000235:genetics; D017354:Point Mutation / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011500:Protein Synthesis Inhibitors; D011956:Receptors, Cell Surface; C472780:SORCS1 protein, human; D014443:Tyrosine; D003513:Cycloheximide