Publication
Title
The oxygen sensor PHD2 controls dendritic spines and synapses via modification of filamin A
Author
Abstract
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.
Language
English
Source (journal)
Cell reports
Publication
2016
ISSN
2211-1247
Volume/pages
14:11(2016), p. 2653-2667
ISI
000372499000015
Full text (Publisher's DOI)
Full text (open access)
UAntwerpen
Faculty/Department
Research group
[E?say:metaLocaldata.cgzprojectinf]
Mechanisms of brain wiring in normal and pathological conditions (WIBRAIN).
Neuroelectronics and nanotechnology: towards a multidisciplinary approach for the science and engineering of neuronal networks (NAMASEN).
A quantum leap: from a spike-centered brrain universe to its underlying synaptic landscape (BRAINLEAP).
A collaborative training program to develop multi-electrode array (MEA) platforms to understand synaptic function and treat diseases of the nervous system (NEUROACT).
Imaging neural activity at the cellular- and network-levels by optically detected diamond spin-magnetometers and nanoparticle FRET sensors.
ASTROFUNC: Molecular Studies of Astrocyte Function in Health and Disease
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 15.03.2016
Last edited 22.08.2017
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