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Verfasst von:Kaufmann, Muriel R. [VerfasserIn]   i
 Barth, Sandra [VerfasserIn]   i
 Konietzko, Uwe [VerfasserIn]   i
 Wu, Bei [VerfasserIn]   i
 Egger, Sascha [VerfasserIn]   i
 Kunze, Reiner [VerfasserIn]   i
 Marti, Hugo [VerfasserIn]   i
 Hick, Meike [VerfasserIn]   i
 Müller, Ulrike C. [VerfasserIn]   i
 Camenisch, Gieri [VerfasserIn]   i
 Wenger, Roland H. [VerfasserIn]   i
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

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