title: FBL2 regulates amyloid precursor protein (APP) metabolism by promoting ubiquitination-dependent APP degradation and inhibition of APP endocytosis.
abstract: The ubiquitin-proteasome pathway is a major protein degradation pathway whose dysfunction is now widely accepted as a cause of neurodegenerative diseases, including Alzheimer's disease. Here we demonstrate that the F-box and leucine rich repeat protein2 (FBL2), a component of the E3 ubiquitin ligase complex, regulates amyloid precursor protein (APP) metabolism through APP ubiquitination. FBL2 overexpression decreased the amount of secreted amyloid β (Aβ) peptides and sAPPβ, whereas FBL2 mRNA knockdown by siRNA increased these levels. FBL2 overexpression also decreased the amount of intracellular Aβ in Neuro2a cells stably expressing APP with Swedish mutation. FBL2 bound with APP specifically at its C-terminal fragment (CTF), which promoted APP/CTF ubiquitination. FBL2 overexpression also accelerated APP proteasome-dependent degradation and decreased APP protein localization in lipid rafts by inhibiting endocytosis. These effects were not observed in an F-box-deleted FBL2 mutant that does not participate in the E3 ubiquitin ligase complex. Furthermore, a reduced insoluble Aβ and Aβ plaque burden was observed in the hippocampus of 7-month-old FBL2 transgenic mice crossed with double-transgenic mice harboring APPswe and PS1(M146V) transgenes. These findings indicate that FBL2 is a novel and dual regulator of APP metabolism through FBL2-dependent ubiquitination of APP.
authors.affiliation: CNS Drug Discovery Unit, Oncology Drug Discovery Unit, Evotec Neurosciences, 8008 Zurich, Switzerland. Watanabe_Tomomichi@takeda.co.jp
authors.forename: Tomomichi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hikichi
authors.forename: Antje
authors.initials: A
authors.lastname: Willuweit
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shintani
authors.forename: Takashi
authors.initials: T
authors.lastname: Horiguchi
mesh_terms: D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004705:Endocytosis / Q000235:genetics; D044783:F-Box Proteins / Q000502:physiology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009433:Neural Inhibition / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D054875:Ubiquitination / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D044783:F-Box Proteins; C122028:FBXL2 protein, human; D010446:Peptide Fragments