The Ubiquitin E3 Ligase Nedd4 Regulates the Expression and Amyloid-β Peptide Export Activity of P-Glycoprotein
The ATP-binding cassette transporter, P-glycoprotein (P-gp), has been demonstrated to facilitate the clearance of amyloid-beta (Aβ) 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 Aβ 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 Aβ clearance from the brain.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:23 |
|---|---|
| Enthalten in: |
International journal of molecular sciences - 23(2022), 3 vom: 18. Jan. |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Chai, Amanda B [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 08.03.2022 Date Revised 08.03.2022 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.3390/ijms23031019 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM336950381 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM336950381 | ||
| 003 | DE-627 | ||
| 005 | 20231225233316.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3390/ijms23031019 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1123.xml |
| 035 | |a (DE-627)NLM336950381 | ||
| 035 | |a (NLM)35162941 | ||
| 035 | |a (PII)1019 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Chai, Amanda B |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The Ubiquitin E3 Ligase Nedd4 Regulates the Expression and Amyloid-β Peptide Export Activity of P-Glycoprotein |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 08.03.2022 | ||
| 500 | |a Date Revised 08.03.2022 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a The ATP-binding cassette transporter, P-glycoprotein (P-gp), has been demonstrated to facilitate the clearance of amyloid-beta (Aβ) 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 Aβ 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 Aβ clearance from the brain | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a ABCB1 | |
| 650 | 4 | |a Nedd4 | |
| 650 | 4 | |a P-glycoprotein | |
| 650 | 4 | |a amyloid-beta | |
| 650 | 4 | |a ubiquitin E3 ligase | |
| 650 | 7 | |a ABCB1 protein, human |2 NLM | |
| 650 | 7 | |a APP protein, human |2 NLM | |
| 650 | 7 | |a ATP Binding Cassette Transporter, Subfamily B |2 NLM | |
| 650 | 7 | |a Amyloid beta-Protein Precursor |2 NLM | |
| 650 | 7 | |a Fluoresceins |2 NLM | |
| 650 | 7 | |a calcein AM |2 NLM | |
| 650 | 7 | |a 148504-34-1 |2 NLM | |
| 650 | 7 | |a Nedd4 Ubiquitin Protein Ligases |2 NLM | |
| 650 | 7 | |a EC 2.3.2.26 |2 NLM | |
| 650 | 7 | |a Nedd4 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.3.2.26 |2 NLM | |
| 700 | 1 | |a Callaghan, Richard |e verfasserin |4 aut | |
| 700 | 1 | |a Gelissen, Ingrid C |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t International journal of molecular sciences |d 2008 |g 23(2022), 3 vom: 18. Jan. |w (DE-627)NLM185552161 |x 1422-0067 |7 nnns |
| 773 | 1 | 8 | |g volume:23 |g year:2022 |g number:3 |g day:18 |g month:01 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.3390/ijms23031019 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 23 |j 2022 |e 3 |b 18 |c 01 | ||