title: SorLA complement-type repeat domains protect the amyloid precursor protein against processing.
abstract: SorLA is a neuronal sorting receptor that is genetically associated with Alzheimer disease. SorLA interacts directly with the amyloid precursor protein (APP) and affects the processing of the precursor, leading to a decreased generation of the amyloid-β peptide. The SorLA complement-type repeat (CR) domains associate in vitro with APP, but the precise molecular determinants of SorLA·APP complex formation and the mechanisms responsible for the effect of binding on APP processing have not yet been elucidated. Here, we have generated protein expression constructs for SorLA devoid of the 11 CR-domains and for two SorLA mutants harboring substitutions of the fingerprint residues in the central CR-domains. We generated SH-SY5Y cell lines that stably express these SorLA variants to study the binding and processing of APP using co-immunoprecipitation and Western blotting/ELISAs, respectively. We found that the SorLA CR-cluster is essential for interaction with APP and that deletion of the CR-cluster abolishes the protection against APP processing. Mutation of identified fingerprint residues in the SorLA CR-domains leads to changes in the O-linked glycosylation of APP when expressed in SH-SY5Y cells. Our results provide novel information on the mechanisms behind the influence of SorLA activity on APP metabolism by controlling post-translational glycosylation in the Golgi, suggesting new strategies against amyloidogenesis in Alzheimer disease.
authors.affiliation: From the Lundbeck Foundation Research Center MIND, Danish Research Institute of Translational Neuroscience Nordic-EMBL Partnership (DANDRITE), Department of Biomedicine, Aarhus University, Ole Worms Allé 3, DK-8000 AarhusC, Denmark and.
authors.forename: Arnela
authors.initials: A
authors.lastname: Mehmedbasic
authors.affiliation: From the Lundbeck Foundation Research Center MIND, Danish Research Institute of Translational Neuroscience Nordic-EMBL Partnership (DANDRITE), Department of Biomedicine, Aarhus University, Ole Worms Allé 3, DK-8000 AarhusC, Denmark and.
authors.forename: Sofie K
authors.initials: SK
authors.lastname: Christensen
authors.affiliation: the Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Nilsson
authors.affiliation: the Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
authors.forename: Ulla
authors.initials: U
authors.lastname: Rüetschi
authors.affiliation: From the Lundbeck Foundation Research Center MIND, Danish Research Institute of Translational Neuroscience Nordic-EMBL Partnership (DANDRITE), Department of Biomedicine, Aarhus University, Ole Worms Allé 3, DK-8000 AarhusC, Denmark and.
authors.forename: Camilla
authors.initials: C
authors.lastname: Gustafsen
authors.affiliation: From the Lundbeck Foundation Research Center MIND, Danish Research Institute of Translational Neuroscience Nordic-EMBL Partnership (DANDRITE), Department of Biomedicine, Aarhus University, Ole Worms Allé 3, DK-8000 AarhusC, Denmark and.
authors.forename: Annemarie Svane Aavild
authors.initials: AS
authors.lastname: Poulsen
authors.affiliation: From the Lundbeck Foundation Research Center MIND, Danish Research Institute of Translational Neuroscience Nordic-EMBL Partnership (DANDRITE), Department of Biomedicine, Aarhus University, Ole Worms Allé 3, DK-8000 AarhusC, Denmark and.
authors.forename: Rikke W
authors.initials: RW
authors.lastname: Rasmussen
authors.affiliation: From the Lundbeck Foundation Research Center MIND, Danish Research Institute of Translational Neuroscience Nordic-EMBL Partnership (DANDRITE), Department of Biomedicine, Aarhus University, Ole Worms Allé 3, DK-8000 AarhusC, Denmark and.
authors.forename: Anja N
authors.initials: AN
authors.lastname: Fjorback
authors.affiliation: the Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Larson
authors.affiliation: From the Lundbeck Foundation Research Center MIND, Danish Research Institute of Translational Neuroscience Nordic-EMBL Partnership (DANDRITE), Department of Biomedicine, Aarhus University, Ole Worms Allé 3, DK-8000 AarhusC, Denmark and o.andersen@biomed.au.dk.
authors.forename: Olav M
authors.initials: OM
authors.lastname: Andersen
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001665:Binding Sites; D045744:Cell Line, Tumor; D006031:Glycosylation; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport
chemical_list: D016564:Amyloid beta-Protein Precursor; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; C102582:SORL1 protein, human
keywords: Alzheimer Disease; Amyloid Precursor Protein (APP); CR-domains; Fingerprint Residues; Golgi; Intracellular Trafficking; Membrane Protein; O-Glycosylation; SorLA