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SorLA CR-Domains Protect the Amyloid Precursor Protein against Processing.

Journal article
Authors Arnela Mehmedbasic
Sofie K Christensen
Jonas Nilsson
Ulla Rüetschi
Camilla Gustafsen
Annemarie Svane Aavild Poulsen
Rikke W Rasmussen
Anja N Fjorback
Göran Larson
Olav M Andersen
Published in The Journal of biological chemistry
Volume 290
Pages 3359-3376
ISSN 1083-351X
Publication year 2015
Published at Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine
Pages 3359-3376
Language en
Subject categories Cell and Molecular Biology, Medical cell biology, Clinical Laboratory Medicine, Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)


SorLA is a neuronal sorting receptor that is genetically associated with Alzheimer's 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 (Aβ) 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/ELISA assays, 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's disease.

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