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

Abstract

SummaryNeuronal 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.

Tsc1 haploinsufficiency is sufficient to increase dendritic patterning and Filamin A levels

“…Nevertheless, our finding has several important implications. First, it was also recently reported that increased FLNA levels can alter spine morphology [27] in addition to dendrites as shown here. A change in dendritic morphology, including spine morphology is a hallmark of several disorders associated with cognitive and deficits [15;28].…”

New Insights into Protein Hydroxylation and Its Important Role in Human Diseases

“…Hypoxia was reported to induce reversible spine regression, an effort by neurons to avoid the energy crisis by decreasing synaptic transmission [116]. Filamin A (FLNA) is an important actin cross-linker.…”

“…[116] showed that under normoxic conditions, PHD2/EglN1 promotes FLNA hydroxylation on multiple proline residues, including Pro2309, Pro2316 and possibly Pro2312, which will lead to FLNA binding with pVHL E3 ligase complex and degradation by the proteasome. Inhibition of PHD2/EglN1 activity by genetic approach ( PHD2/EglN1 loss), pharmacological approach (such as DMOG) or physiological relevant condition (such as hypoxia) can lead to FLNA stabilization and immature filopodium-like dendritic protrusion, therefore inducing spine regression and reduced synaptic density [116]. Since FLNA has to be precisely regulated in order to prevent neurological defects, PHD2/EglN1 -mediated FLNA hydroxylation and its subsequent regulation by pVHL provides a molecular mechanism for its tight regulation in neurological context in vivo [116].…”

Filamin, a synaptic organizer in Drosophila, determines glutamate receptor composition and membrane growth

“…In lysates of the mammalian brain, filamin associates with known synaptic proteins such as Shank3, Neuroligin 3, and Kv4.2 (Petrecca et al, 2000; Sakai et al, 2011; Shen et al, 2015). A recent report indicated that filamin degradation promotes a transition from immature filopodia to mature dendritic spines (Segura et al, 2016), a phenomenon that is likely to be related to the actin-bundling properties of the long isoform of filamin. Data in the present study have uncovered a novel pathway that does not require the actin-binding domain of filamin.…”