title: SORLA regulates calpain-dependent degradation of synapsin.
abstract: Sorting-related receptor with A-type repeats (SORLA) is an intracellular sorting receptor in neurons and a major risk factor for Alzheimer disease.
  
  
  
  Here, we performed global proteome analyses in the brain of SORLA-deficient mice followed by biochemical and histopathologic studies to identify novel neuronal pathways affected by receptor dysfunction.
  
  
  
  We demonstrate that the lack of SORLA results in accumulation of phosphorylated synapsins in cortex and hippocampus. We propose an underlying molecular mechanism by demonstrating that SORLA interacts with phosphorylated synapsins through 14-3-3 adaptor proteins to deliver synapsins to calpain-mediated proteolytic degradation.
  
  
  
  Our results suggest a novel function for SORLA which is in control of synapsin degradation, potentially impacting on synaptic vesicle endocytosis and/or exocytosis.
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité-University Medicine, Berlin, Germany; Department of Psychiatry and Psychotherapy, Saarland University Hospital, Saarland University, Homburg, Germany. Electronic address: daniela.hartl@uniklinikum-saarland.de.
authors.forename: Daniela
authors.initials: D
authors.lastname: Hartl
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité-University Medicine, Berlin, Germany.
authors.forename: Grit
authors.initials: G
authors.lastname: Nebrich
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité-University Medicine, Berlin, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Klein
authors.affiliation: Leibniz Institute for Molecular Pharmacology, Berlin, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Stephanowitz
authors.affiliation: Leibniz Institute for Molecular Pharmacology, Berlin, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Krause
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany. Electronic address: michael.rohe@abbvie.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Rohe
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000544:Alzheimer Disease; D000818:Animals; D002154:Calpain / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D059748:Proteolysis; D020543:Proteome; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D016704:Synapsins / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D026901:Membrane Transport Proteins; D020543:Proteome; D011973:Receptors, LDL; C491168:Sorl1 protein, mouse; D016704:Synapsins; D002154:Calpain
keywords: Alzheimer's disease; Risk factor; SORLA; Sorl1; Sporadic AD; Synapse