Parp3 promotes astrocytic differentiation through a tight regulation of Nox4-induced ROS and mTorc2 activation

José-Manuel Rodriguez-Vargas,Kathline Martin-Hernandez,Jean-Christophe Amé,Nicolas Kunath,Françoise Dantzer,Rajikala Suganthan,Wei Wang,F Javier Oliver,Jing Ye,Magnar Bjørås

doi:10.1038/s41419-020-03167-5

Abstract

Parp3 is a member of the Poly(ADP-ribose) polymerase (Parp) family that has been characterized for its functions in strand break repair, chromosomal rearrangements, mitotic segregation and tumor aggressiveness. Yet its physiological implications remain unknown. Here we report a central function of Parp3 in the regulation of redox homeostasis in continuous neurogenesis in mice. We show that the absence of Parp3 provokes Nox4-induced oxidative stress and defective mTorc2 activation leading to inefficient differentiation of post-natal neural stem/progenitor cells to astrocytes. The accumulation of ROS contributes to the decreased activity of mTorc2 as a result of an oxidation-induced and Fbxw7-mediated ubiquitination and degradation of Rictor. In vivo, mTorc2 signaling is compromised in the striatum of naïve post-natal Parp3-deficient mice and 6 h after acute hypoxia-ischemia. These findings reveal a physiological function of Parp3 in the tight regulation of striatal oxidative stress and mTorc2 during astrocytic differentiation and in the acute phase of hypoxia-ischemia.

Highlights

1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction In the developing and adult mammalian brain, continuous neurogenesis and brain plasticity depend on the sustained activity of neural stem/progenitor cells (NPSCs) which mainly reside in two neurogenic niches: the subventricular zone (SVZ) in the walls of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus
To investigate cell-intrinsic properties of Poly(ADP-ribose) polymerase (Parp)[3] in neurogenesis, we used the neurosphere assay to quantify the capacity of NPSC to form multipotent clonal aggregates and to differentiate into glial lineage[28,29]
NPSCs isolated from the brain of Parp3–/– post-natal mice were not affected in their ability to form primary neurospheres and they displayed normal levels of proliferation and selfrenewal compared to Parp3+/+ NPSCs (Supplementary Fig. 1)

Summary

Introduction

In the developing and adult mammalian brain, continuous neurogenesis and brain plasticity depend on the sustained activity of neural stem/progenitor cells (NPSCs) which mainly reside in two neurogenic niches: the subventricular zone (SVZ) in the walls of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus. In both regions, NPSCs self-renew, migrate and retain the ability to differentiate into neurons, astrocytes and oligodendrocytes. Astrocytes generate high levels of mitochondrial ROS5.

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