Journal
CELL METABOLISM
Volume 23, Issue 2, Pages 280-291Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2015.12.007
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Funding
- Research Foundation-Flanders (FWO)
- FP7 Marie Curie Intra-European Fellowship
- Pegasus Marie Curie-FWO
- Agency for Innovation by Science and Technology in Flanders (IWT)
- Belgian Science Policy [IUAP P7/ 03]
- Flemish Government
- FWO [G.0671.12N, 1.5.244.11N]
- Foundation Leducq Transatlantic Network (ARTEMIS)
- A cure for ALS from ALS Liga Belgium
- Motor Neuron Disease Association
- ALS Association [C44128]
- European Research Council (ERC) [340429]
- European Union [259867]
- Leuven University Fund - Opening the Future
- E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders & Geneeskundige Stichting Koningin Elisabeth
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The oxygen-sensing prolyl hydroxylase domain proteins (PHDs) regulate cellular metabolism, but their role in neuronal metabolism during stroke is unknown. Here we report that PHD1 deficiency provides neuroprotection in a murine model of permanent brain ischemia. This was not due to an increased collateral vessel network. Instead, PHD1(-/-) neurons were protected against oxygen-nutrient deprivation by reprogramming glucose metabolism. Indeed, PHD1(-/-) neurons enhanced glucose flux through the oxidative pentose phosphate pathway by diverting glucose away from glycolysis. As a result, PHD1(-/-) neurons increased their redox buffering capacity to scavenge oxygen radicals in ischemia. Intracerebroventricular injection of PHD1-antisense oligonucleotides reduced the cerebral infarct size and neurological deficits following stroke. These data identify PHD1 as a regulator of neuronal metabolism and a potential therapeutic target in ischemic stroke.
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