| Online-Ressource |
Verfasst von: | Kaufmann, Muriel R. [VerfasserIn]  |
| Barth, Sandra [VerfasserIn]  |
| Konietzko, Uwe [VerfasserIn]  |
| Wu, Bei [VerfasserIn]  |
| Egger, Sascha [VerfasserIn]  |
| Kunze, Reiner [VerfasserIn]  |
| Marti, Hugo [VerfasserIn]  |
| Hick, Meike [VerfasserIn]  |
| Müller, Ulrike C. [VerfasserIn]  |
| Camenisch, Gieri [VerfasserIn]  |
| Wenger, Roland H. [VerfasserIn]  |
Titel: | Dysregulation of hypoxia-inducible factor by presenilin/γ-secretase loss-of-function mutations |
Verf.angabe: | Muriel R. Kaufmann, Sandra Barth, Uwe Konietzko, Bei Wu, Sascha Egger, Reiner Kunze, Hugo H. Marti, Meike Hick, Ulrike Müller, Gieri Camenisch, and Roland H. Wenger |
E-Jahr: | 2013 |
Jahr: | January 30, 2013 |
Umfang: | 12 S. |
Teil: | volume:33 |
| year:2013 |
| number:5 |
| pages:1915-1926 |
| extent:12 |
Fussnoten: | Gesehen am 23.04.2021 |
Titel Quelle: | Enthalten in: The journal of neuroscience |
Ort Quelle: | Washington, DC : Soc., 1981 |
Jahr Quelle: | 2013 |
Band/Heft Quelle: | 33(2013), 5, Seite 1915-1926 |
ISSN Quelle: | 1529-2401 |
Abstract: | Presenilin (PSEN) 1 and 2 are the catalytic components of the γ-secretase complex, which cleaves a variety of proteins, including the amyloid precursor protein (APP). Proteolysis of APP leads to the formation of the APP intracellular domain (AICD) and amyloid β that is crucially involved in the pathogenesis of Alzheimer's disease. Prolyl-4-hydroxylase-domain (PHD) proteins regulate the hypoxia-inducible factors (HIFs), the master regulators of the hypoxic response. We previously identified the FK506 binding protein 38 (FKBP38) as a negative regulator of PHD2. Genetic ablation of PSEN1/2 has been shown to increase FKBP38 protein levels. Therefore, we investigated the role of PSEN1/2 in the oxygen sensing pathway using a variety of genetically modified cell and mouse lines. Increased FKBP38 protein levels and decreased PHD2 protein levels were found in PSEN1/2-deficient mouse embryonic fibroblasts and in the cortex of forebrain-specific PSEN1/2 conditional double knock-out mice. Hypoxic HIF-1α protein accumulation and transcriptional activity were decreased, despite reduced PHD2 protein levels. Proteolytic γ-secretase function of PSEN1/2 was needed for proper HIF activation. Intriguingly, PSEN1/2 mutations identified in Alzheimer patients differentially affected the hypoxic response, involving the generation of AICD. Together, our results suggest a direct role for PSEN in the regulation of the oxygen sensing pathway via the APP/AICD cleavage cascade. |
DOI: | doi:10.1523/JNEUROSCI.3402-12.2013 |
URL: | Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.
Volltext ; Verlag: https://doi.org/10.1523/JNEUROSCI.3402-12.2013 |
| Volltext: https://www.jneurosci.org/content/33/5/1915 |
| DOI: https://doi.org/10.1523/JNEUROSCI.3402-12.2013 |
Datenträger: | Online-Ressource |
Sprache: | eng |
K10plus-PPN: | 1755791070 |
Verknüpfungen: | → Zeitschrift |
Dysregulation of hypoxia-inducible factor by presenilin/γ-secretase loss-of-function mutations / Kaufmann, Muriel R. [VerfasserIn]; January 30, 2013 (Online-Ressource)