RRC ID 34816
Author Watanabe T, Hikichi Y, Willuweit A, Shintani Y, Horiguchi T.
Title FBL2 regulates amyloid precursor protein (APP) metabolism by promoting ubiquitination-dependent APP degradation and inhibition of APP endocytosis.
Journal J Neurosci
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.
Volume 32(10)
Pages 3352-65
Published 2012-3-7
DOI 10.1523/JNEUROSCI.5659-11.2012
PII 32/10/3352
PMID 22399757
PMC PMC6621050
MeSH Amino Acid Sequence Amyloid beta-Protein Precursor / antagonists & inhibitors Amyloid beta-Protein Precursor / genetics Amyloid beta-Protein Precursor / metabolism* Animals Cell Line, Tumor Cells, Cultured Endocytosis* / genetics F-Box Proteins / physiology* Female HEK293 Cells Humans Mice Mice, Inbred C57BL Mice, Transgenic Molecular Sequence Data Neural Inhibition* / genetics Peptide Fragments / genetics Peptide Fragments / metabolism Protein Binding / genetics Ubiquitination* / genetics
IF 5.674
Times Cited 40
DNA material pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393) CSII-CMV-MCS (RDB04377).