Parp3 promotes astrocytic differentiation through a tight regulation of Nox4-induced ROS and mTorc2 activation
Rodriguez-Vargas, José-Manuel; Martin-Hernandez, Kathline; Wang, Wei; Kunath, Nicolas; Suganthan, Rajikala; Amé, Jean-Christophe; Francisco, Javier Oliver Pozo; Ye, Jing; Bjørås, Magnar; Dantzer, Françoise
Peer reviewed, Journal article
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Date
2020Metadata
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Original version
10.1038/s41419-020-03167-5Abstract
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 oxidationinduced 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.