Dysregulation of Hypoxia-Inducible Factor by Presenilin/ Gamma-Secretase Loss-of-Function Mutations

Presenilin (PSEN) 1 and 2 are the catalytic components of the Gamma-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 Beta 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.Wepreviously 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 knockout mice. Hypoxic HIF-1alpha protein accumulation and transcriptional activity were decreased, despite reduced PHD2 protein levels. Proteolytic gamma-secretase function ofPSEN1/2wasneeded for proper HIF activation. Intriguingly, PSEN1/2 mutations identified in Alzheimer patients differentially affected the hypoxicresponse, 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: https://doi.org/10.1523/JNEUROSCI.3402-12.2013 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-73057 Published Version Originally published at: Kaufmann, M R; Barth, S; Konietzko, U; Wu, Bei; Egger, Sascha; Kunze, Reiner; Marti, Hugo H; Hick, Meike; Müller, Ulrike; Camenisch, G; Wenger, R H (2013). Dysregulation of Hypoxia-Inducible Factor by Presenilin/ Gamma-Secretase Loss-of-Function Mutations. Journal of Neuroscience, 33(5):1915-1926. DOI: https://doi.org/10.1523/JNEUROSCI.3402-12.2013