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 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.
Institute of Physiology and Zürich Center for Integrative Human Physiology, University of Zürich, CH-8057 Zürich, Switzerland.
Muriel R
MR
Kaufmann
Sandra
S
Barth
Uwe
U
Konietzko
Bei
B
Wu
Sascha
S
Egger
Reiner
R
Kunze
Hugo H
HH
Marti
Meike
M
Hick
Ulrike
U
Müller
Gieri
G
Camenisch
Roland H
RH
Wenger
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
D016564:Amyloid beta-Protein Precursor; D051793:Hypoxia-Inducible Factor 1; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases