USIAS Fellows seminar - An emerging actor in neurogenesis: PARP3

By Françoise Dantzer (Fellow 2017)

An emerging actor in neurogenesis: PARP3 and astrocytic differentiation

Poly (ADP-ribose) polymerase (PARP, 17 members) is a family of proteins involved in a number of cellular processes such as DNA repair, genome stability and cell death. In particular  PARP1 has emerged as a promising target in cancer therapy.

The main role of PARPs is to detect, initiate and promote an immediate cellular response to DNA strand breaks by stimulating the enzymatic machinery involved in DNA repair. The USIAS project aims to unravel roles of these repair enzymes beyond DNA repair. More specifically, while PARP3, the third member of this family has been characterized for its prominent functions in DNA repair and tumour progression, the USIAS project investigated a new line of research exploring the role of this protein in neurogenesis. 

Due to their regenerative potentials, neural progenitor stem cells (NPSCs) have been implicated in the treatment of neurodegenerative diseases and injuries to the brain, such as hypoxia-ischemia in the immature brain in preterm neonates, and brain stroke.

NPSCs can proliferate and generate neurons, astrocytes, and oligodendrocytes in the central nervous systems. Astrocytic differentiation is indispensable in neurogenesis and cerebral cortical development. Astrocytes play crucial roles in maintaining the normal cognitive network of the cerebral cortex, and astrocyte dysfunction is associated with certain central nervous system disorders.

We show that Parp3 controls the production of Nox4-induced reactive Oxygen species (ROS) and governs the activation of mTorc2 signaling during astrocytic differentiation. In vivo, we show that the Parp3-mTorc2 axis prevails in the striatum of post-natal mice and shortly after 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.

Elucidating the role of PARP3 in NPSC differentiation and understanding the consequences for neurogenesis and brain repair provides an important new level of knowledge, which can in time become the basis of treatment.

More information: PARP3 in continuous and stress-induced neurogenesis