| RRC ID |
34816
|
| 著者 |
Watanabe T, Hikichi Y, Willuweit A, Shintani Y, Horiguchi T.
|
| タイトル |
FBL2 regulates amyloid precursor protein (APP) metabolism by promoting ubiquitination-dependent APP degradation and inhibition of APP endocytosis.
|
| ジャーナル |
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.
|
| 巻・号 |
32(10)
|
| ページ |
3352-65
|
| 公開日 |
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
|
| 引用数 |
40
|
|
WOS 分野
|
NEUROSCIENCES
|
| リソース情報 |
| 遺伝子材料 |
pCAG-HIVgp (RDB04394)
pCMV-VSV-G-RSV-Rev (RDB04393)
CSII-CMV-MCS (RDB04377). |
