title: Retromer binds the FANSHY sorting motif in SorLA to regulate amyloid precursor protein sorting and processing.
abstract: sorLA is a sorting receptor for amyloid precursor protein (APP) genetically linked to Alzheimer's disease (AD). Retromer, an adaptor complex in the endosome-to-Golgi retrieval pathway, has been implicated in APP transport because retromer deficiency leads to aberrant APP sorting and processing and levels of retromer proteins are altered in AD. Here we report that sorLA and retromer functionally interact in neurons to control trafficking and amyloidogenic processing of APP. We have identified a sequence (FANSHY) in the cytoplasmic domain of sorLA that is recognized by the VPS26 subunit of the retromer complex. Accordingly, we characterized the interaction between the retromer complex and sorLA and determined the role of retromer on sorLA-dependent sorting and processing of APP. Mutations in the VPS26 binding site resulted in receptor redistribution to the endosomal network, similar to the situation seen in cells with VPS26 knockdown. The sorLA mutant retained APP-binding activity but, as opposed to the wild-type receptor, misdirected APP into a distinct non-Golgi compartment, resulting in increased amyloid processing. In conclusion, our data provide a molecular link between reduced retromer expression and increased amyloidogenesis as seen in patients with sporadic AD.
authors.affiliation: The Lundbeck Foundation Research Centre MIND, Department of Biomedicine, Aarhus University, and MIND Centre, Stereology and Electron Microscopy Laboratory, Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
authors.forename: Anja W
authors.initials: AW
authors.lastname: Fjorback
authors.forename: Matthew
authors.initials: M
authors.lastname: Seaman
authors.forename: Camilla
authors.initials: C
authors.lastname: Gustafsen
authors.forename: Arnela
authors.initials: A
authors.lastname: Mehmedbasic
authors.forename: Suzanne
authors.initials: S
authors.lastname: Gokool
authors.forename: Chengbiao
authors.initials: C
authors.lastname: Wu
authors.forename: Daniel
authors.initials: D
authors.lastname: Militz
authors.forename: Vanessa
authors.initials: V
authors.lastname: Schmidt
authors.forename: Peder
authors.initials: P
authors.lastname: Madsen
authors.forename: Jens R
authors.initials: JR
authors.lastname: Nyengaard
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Willnow
authors.forename: Erik Ilsø
authors.initials: EI
authors.lastname: Christensen
authors.forename: William B
authors.initials: WB
authors.lastname: Mobley
authors.forename: Anders
authors.initials: A
authors.lastname: Nykjær
authors.forename: Olav M
authors.initials: OM
authors.lastname: Andersen
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D016716:PC12 Cells; D011485:Protein Binding / Q000235:genetics; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D046188:Protein Modification, Translational / Q000235:genetics / Q000502:physiology*; D021381:Protein Transport / Q000235:genetics; D051381:Rats
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; C102582:SORL1 protein, human