Poly(ADP-ribose) polymerase 1 is a novel target to promote axonal regeneration

Abstract

Therapeutic options for the restoration of neurological functions after acute axonal injury are severely limited. In addition to limiting neuronal loss, effective treatments face the challenge of restoring axonal growth within an injury environment where inhibitory molecules from damaged myelin and activated astrocytes act as molecular and physical barriers. Overcoming these barriers to permit axon growth is critical for the development of any repair strategy in the central nervous system. Here, we identify poly(ADP-ribose) polymerase 1 (PARP1) as a previously unidentified and critical mediator of multiple growth-inhibitory signals. We show that exposure of neurons to growth-limiting molecules-such as myelin-derived Nogo and myelin-associated glycoprotein-or reactive astrocyte-produced chondroitin sulfate proteoglycans activates PARP1, resulting in the accumulation of poly(ADP-ribose) in the cell body and axon and limited axonal growth. Accordingly, we find that pharmacological inhibition or genetic loss of PARP1 markedly facilitates axon regeneration over nonpermissive substrates. Together, our findings provide critical insights into the molecular mechanisms of axon growth inhibition and identify PARP1 as an effective target to promote axon regeneration.poly(ADP-ribose) polymerase | PARP1 | PAR | axon | regeneration

Inhibition of Poly-ADP-Ribosylation Fails to Increase Axonal Regeneration or Improve Functional Recovery after Adult Mammalian CNS Injury

“…1 A– D, P = 0.0004 a soluble and P = 0.0032 b insoluble). This PARylation increase is similar to that described in Brochier et al (2015). After 5 d of veliparib administration to naive mice, the level of PARylated protein was suppressed within the retinal tissue (Fig.…”

“…One study found that PARP activity was required for inhibitory factors such as Nogo and MAG to limit axon outgrowth in cultured neurons (Brochier et al, 2015). Further, PARP itself was found to be upregulated by CNS injury, suggesting it might function in axon regeneration (Brochier et al, 2015).…”

“…One study found that PARP activity was required for inhibitory factors such as Nogo and MAG to limit axon outgrowth in cultured neurons (Brochier et al, 2015). Further, PARP itself was found to be upregulated by CNS injury, suggesting it might function in axon regeneration (Brochier et al, 2015). A second study found that deletion or inhibition of PARPs did in fact enhance axon regeneration, both in vivo for the nematode Caenorhabditis elegans and in vitro for mammalian cerebral cortical cultures (Byrne et al, 2016).…”

Intrinsic mechanisms of neuronal axon regeneration

“…Exposure of neurons to growth-limiting molecules, such as myelin-derived Nogo, myelin-associated glycoprotein (MAG) and chondroitin sulfate proteoglycans (CSPGs), activates the enzyme polymerase 1 (PARP1), causing the accumulation of poly(ADP-ribose), which limits axon growth 84 . Pharmacological inhibition or genetic deletion of PARP1 facilitates axon regeneration over non-permissive substrates in cultured cortical and DRG neurons by a mechanism that is independent of histone poly(ADP-ribosylation) (PARylation) or the activation of regeneration-associated genes (RAGs) 84 . This system is conserved across species, as removal of poly(ADP-ribose) from proteins by poly(ADP-ribose) glycohydrolases (PARGs) enhances axon regeneration in C. elegans neurons 85 .…”

“…This system is conserved across species, as removal of poly(ADP-ribose) from proteins by poly(ADP-ribose) glycohydrolases (PARGs) enhances axon regeneration in C. elegans neurons 85 . Additionally, PARP is locally activated in the injured optic nerve 84 ; however, inhibition of PARP is insufficient to enhance axonal regeneration in either the optic nerve crush injury or thoracic spinal cord injury mouse models 86 . This is consistent with the fact that downstream of Nogo, MAG and CSPGs, other pathways cause growth cone collapse 87 .…”