title: Distinct Functions for Anterograde and Retrograde Sorting of SORLA in Amyloidogenic Processes in the Brain.
abstract: SORLA is a neuronal sorting receptor implicated both in sporadic and familial forms of AD. SORLA reduces the amyloidogenic burden by two mechanisms, either by rerouting internalized APP molecules from endosomes to the trans-Golgi network (TGN) to prevent proteolytic processing or by directing newly produced Aβ to lysosomes for catabolism. Studies in cell lines suggested that the interaction of SORLA with cytosolic adaptors retromer and GGA is required for receptor sorting to and from the TGN. However, the relevance of anterograde or retrograde trafficking for SORLA activity in vivo remained largely unexplored. Here, we generated mouse models expressing SORLA variants lacking binding sites for GGA or retromer to query this concept in the brain. Disruption of retromer binding resulted in a retrograde-sorting defect with accumulation of SORLA in endosomes and depletion from the TGN, and in an overall enhanced APP processing. In contrast, disruption of the GGA interaction did not impact APP processing but caused increased brain Aβ levels, a mechanism attributed to a defect in anterograde lysosomal targeting of Aβ. Our findings substantiated the significance of adaptor-mediated sorting for SORLA activities in vivo, and they uncovered that anterograde and retrograde sorting paths may serve discrete receptor functions in amyloidogenic processes.
  
  
  CONCLUSIONS
  SORLA is a sorting receptor that directs target proteins to distinct intracellular compartments in neurons. SORLA has been identified as a genetic risk factor for sporadic, but recently also for familial forms of AD. To confirm the relevance of SORLA sorting for AD processes in the brain, we generated mouse lines, which express trafficking mutants instead of the wild-type form of this receptor. Studying neuronal activities in these mutant mice, we dissected distinct trafficking routes for SORLA guided by two cytosolic adaptors termed GGA and retromer. We show that these sorting pathways serve discrete functions in control of amyloidogenic processes and may represent unique therapeutic targets to interfere with specific aspects of neurodegenerative processes in the diseased brain.
authors.affiliation: Max Delbrueck Center for Molecular Medicine, D-13125 Berlin, Germany and.
authors.forename: Sonya B
authors.initials: SB
authors.lastname: Dumanis
authors.affiliation: Max Delbrueck Center for Molecular Medicine, D-13125 Berlin, Germany and.
authors.forename: Tilman
authors.initials: T
authors.lastname: Burgert
authors.affiliation: Max Delbrueck Center for Molecular Medicine, D-13125 Berlin, Germany and.
authors.forename: Safak
authors.initials: S
authors.lastname: Caglayan
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus, Denmark.
authors.forename: Annette
authors.initials: A
authors.lastname: Füchtbauer
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus, Denmark.
authors.forename: Ernst-Martin
authors.initials: EM
authors.lastname: Füchtbauer
authors.affiliation: Max Delbrueck Center for Molecular Medicine, D-13125 Berlin, Germany and.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Schmidt
authors.affiliation: Max Delbrueck Center for Molecular Medicine, D-13125 Berlin, Germany and willnow@mdc-berlin.de.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Willnow
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D011992:Endosomes / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000166:cytology; D026502:LDL-Receptor Related Proteins / Q000378:metabolism / Q000502:physiology*; D008247:Lysosomes / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D022661:RNA, Untranslated / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C407306:GGA adaptor proteins; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D022661:RNA, Untranslated; D011993:Recombinant Fusion Proteins; C102582:SORL1 protein, human
keywords: APP processing; SORLA; VPS10P domain receptors; adaptors; protein transport; retromer