The Oxygen Sensor PHD2 Controls Dendritic Spines and Synapses via Modification of Filamin A

Inmaculada Segura (1, 2) , Christian Lange (1, 2) , Ellen Knevels (1, 2) , Anastasiya Moskalyuk (3) , Rocco Pulizzi (3) , Guy Eelen (1, 2) , Thibault Chaze (4) , Cicerone Tudor (5) , Cyril Boulègue (4) , Matthew Holt (5) , Dirk Daelemans (6) , Mariette Matondo (4) , Bart Ghesquière (2) , Michele Giugliano (3, 7, 8) , Carmen Ruiz de almodovar (1, 2) , Mieke Dewerchin (1, 2) , Peter Carmeliet (1, 2)

1 VIB-CCB - Laboratory of Angiogenesis and Vascular Metabolism [Leuven, Belgium]
2 VRC - VIB Vesalius Research Center
3 Universiteit Antwerpen = University of Antwerpen [Antwerpen]
4 Plateforme de Protéomique / Proteomics platform
5 Laboratory of Glia Biology [Leuven, Belgium]
6 Rega Institute for Medical Research [Leuven, België]
7 NERF - Neuroelectronics Research Flanders
8 BMI - EPFL - Brain Mind Institute

Neuronal function is highly sensitive to changes in oxygen levels, but how hypoxia affects dendritic spine formation and synaptogenesis is unknown. Here we report that hypoxia, chemical inhibition of the oxygen-sensing prolyl hydroxylase domain proteins (PHDs), and silencing of Phd2 induce immature filopodium-like dendritic protrusions, promote spine regression, reduce synaptic density, and decrease the frequency of spontaneous action potentials independently of HIF signaling. We identified the actin cross-linker filamin A (FLNA) as a target of PHD2 mediating these effects. In normoxia, PHD2 hydroxylates the proline residues P2309 and P2316 in FLNA, leading to von Hippel-Lindau (VHL)-mediated ubiquitination and proteasomal degradation. In hypoxia, PHD2 inactivation rapidly upregulates FLNA protein levels because of blockage of its proteasomal degradation. FLNA upregulation induces more immature spines, whereas Flna silencing rescues the immature spine phenotype induced by PHD2 inhibition.

Domaines: Sciences du Vivant [q-bio]

Inmaculada Segura, Christian Lange, Ellen Knevels, Anastasiya Moskalyuk, Rocco Pulizzi, et al.. The Oxygen Sensor PHD2 Controls Dendritic Spines and Synapses via Modification of Filamin A. Cell Reports, 2016, 14 (11), pp.2653-2667. ⟨10.1016/j.celrep.2016.02.047⟩. ⟨pasteur-02573601⟩