RT Journal Article
SR Electronic
T1 Dysregulation of Hypoxia-Inducible Factor by Presenilin/γ-Secretase Loss-of-Function Mutations
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 1915
OP 1926
DO 10.1523/JNEUROSCI.3402-12.2013
VO 33
IS 5
A1 Muriel R. Kaufmann
A1 Sandra Barth
A1 Uwe Konietzko
A1 Bei Wu
A1 Sascha Egger
A1 Reiner Kunze
A1 Hugo H. Marti
A1 Meike Hick
A1 Ulrike Müller
A1 Gieri Camenisch
A1 Roland H. Wenger
YR 2013
UL http://www.jneurosci.org/content/33/5/1915.abstract
AB 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.