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

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 path...

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Main Authors: Kaufmann, Muriel R. (Author) , Barth, Sandra (Author) , Konietzko, Uwe (Author) , Wu, Bei (Author) , Egger, Sascha (Author) , Kunze, Reiner (Author) , Marti, Hugo (Author) , Hick, Meike (Author) , Müller, Ulrike C. (Author) , Camenisch, Gieri (Author) , Wenger, Roland H. (Author)
Format: Article (Journal)
Language:English
Published: January 30, 2013
In: The journal of neuroscience
Year: 2013, Volume: 33, Issue: 5, Pages: 1915-1926
ISSN:1529-2401
DOI:10.1523/JNEUROSCI.3402-12.2013
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1523/JNEUROSCI.3402-12.2013
Verlag, lizenzpflichtig, Volltext: https://www.jneurosci.org/content/33/5/1915
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Author Notes: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
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Summary: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.
Item Description:Gesehen am 23.04.2021
Physical Description:Online Resource
ISSN:1529-2401
DOI:10.1523/JNEUROSCI.3402-12.2013

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