The Ubiquitin E3 Ligase Nedd4 Regulates the Expression and Amyloid-ß Peptide Export Activity of P-Glycoprotein.
Int J Mol Sci
; 23(3)2022 Jan 18.
Article
en En
| MEDLINE
| ID: mdl-35162941
ABSTRACT
The ATP-binding cassette transporter, P-glycoprotein (P-gp), has been demonstrated to facilitate the clearance of amyloid-beta (Aß) peptides, exporting the neurotoxic entity out of neurons and out of the brain via the blood-brain barrier. However, its expression and function diminish with age and in Alzheimer's disease. P-gp is known to undergo ubiquitination, a post-translational modification that results in internalisation and/or degradation of the protein. NEDD4-1 is a ubiquitin E3 ligase that has previously been shown to ubiquitinate P-gp and reduce its cell surface expression. However, whether this effect translates into altered P-gp activity remains to be determined. siRNA was used to knockdown the expression of Nedd4 in CHO-APP cells. Western blot analysis confirmed that absence of Nedd4 was associated with increased P-gp protein expression. This was accompanied by increased transport activity, as shown by export of the P-gp substrate calcein-AM, as well as enhanced secretion of Aß peptides, as shown by ELISA. These results implicate Nedd4 in the regulation of P-gp, and highlight a potential approach for restoring or augmenting P-gp expression and function to facilitate Aß clearance from the brain.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Clonación Molecular
/
Precursor de Proteína beta-Amiloide
/
Ubiquitina-Proteína Ligasas Nedd4
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Int J Mol Sci
Año:
2022
Tipo del documento:
Article
País de afiliación:
Australia