title: Retention in endoplasmic reticulum 1 (RER1) modulates amyloid-β (Aβ) production by altering trafficking of γ-secretase and amyloid precursor protein (APP).
abstract: BACKGROUND
  Aβ production is influenced by intracellular trafficking of secretases and amyloid precursor protein (APP).
  
  
  RESULTS
  Retention in endoplasmic reticulum 1 (RER1) regulates the trafficking of γ-secretase and APP, thereby influences Aβ production.
  
  
  CONCLUSIONS
  RER1, an ER retention/retrieval factor for γ-secretase and APP, modulates Aβ production.
  
  
  CONCLUSIONS
  RER1 and its influence on γ-secretase and APP may be implicated for a safe strategy to target Aβ production. The presence of neuritic plaques containing aggregated amyloid-β (Aβ) peptides in the brain parenchyma is a pathological hallmark of Alzheimer disease (AD). Aβ is generated by sequential cleavage of the amyloid β precursor protein (APP) by β- and γ-secretase, respectively. As APP processing to Aβ requires transport through the secretory pathway, trafficking of the substrate and access to the secretases are key factors that can influence Aβ production (Thinakaran, G., and Koo, E. H. (2008) Amyloid precursor protein trafficking, processing, and function. J. Biol. Chem. 283, 29615-29619). Here, we report that retention in endoplasmic reticulum 1 (RER1) associates with γ-secretase in early secretory compartments and regulates the intracellular trafficking of γ-secretase. RER1 overexpression decreases both γ-secretase localization on the cell surface and Aβ secretion and conversely RER1 knockdown increases the level of cell surface γ-secretase and increases Aβ secretion. Furthermore, we find that increased RER1 levels decrease mature APP and increase immature APP, resulting in less surface accumulation of APP. These data show that RER1 influences the trafficking and localization of both γ-secretase and APP, thereby regulating the production and secretion of Aβ peptides.
authors.affiliation: Department of Pharmacology and Therapeutics, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Hyo-Jin
authors.initials: HJ
authors.lastname: Park
authors.forename: Daniil
authors.initials: D
authors.lastname: Shabashvili
authors.forename: Michael D
authors.initials: MD
authors.lastname: Nekorchuk
authors.forename: Eva
authors.initials: E
authors.lastname: Shyqyriu
authors.forename: Joo In
authors.initials: JI
authors.lastname: Jung
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Ladd
authors.forename: Brenda D
authors.initials: BD
authors.lastname: Moore
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Felsenstein
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.forename: Seong-Hun
authors.initials: SH
authors.lastname: Kim
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008562:Membrane Glycoproteins; C109546:RER1 protein, human; D053829:Amyloid Precursor Protein Secretases