Dysregulation of hypoxia-inducible factor by presenilin/γ-secretase loss-of-function mutations

• Verfasst von: Kaufmann, Muriel R. [VerfasserIn]
• Verfasst von: Barth, Sandra [VerfasserIn]
• Verfasst von: Konietzko, Uwe [VerfasserIn]
• Verfasst von: Wu, Bei [VerfasserIn]
• Verfasst von: Egger, Sascha [VerfasserIn]
• Verfasst von: Kunze, Reiner [VerfasserIn]
• Verfasst von: Marti, Hugo [VerfasserIn]
• Verfasst von: Hick, Meike [VerfasserIn]
• Verfasst von: Müller, Ulrike C. [VerfasserIn]
• Verfasst von: Camenisch, Gieri [VerfasserIn]
• Verfasst von: 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
• Teil: year:2013
• Teil: number:5
• Teil: pages:1915-1926
• Teil: 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
• DOI: doi:10.1523/JNEUROSCI.3402-12.2013
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1755791070

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.