Few of the intrinsic mechanisms that regulate axon regeneration after injury are known. To identify genes that regulate axon regeneration, we compared gene expression profiles of FACS-sorted C. elegans GABA motor neurons with high regenerative capacity (conferred by overexpression of DLK-1 MAPKKK) to wild type GABA motor neurons. We detected robust upregulation of both poly(ADP-ribose) glycohydrolases (PARGs), pme-3 and pme-4, in neurons with high regenerative capacity. These data suggest PARG activity might promote axon regeneration. We performed laser axotomy in pme-3 and pme-4 loss-of-function mutants and found that regeneration is impaired. Therefore, PARGs are regeneration-promoting factors.
PARGs degrade poly(ADP-ribose), which is synthesized by poly(ADP-ribose) polymerases (PARPs). Thus, the balance between PARG and PARP activity determines cellular levels of poly(ADP-ribose). The PARG-PARP balance regulates multiple processes including DNA damage response, lifespan, and neurodegeneration. Since PARGs counteract PARP function, we hypothesized that loss of PARP activity would have the opposite effect on axon regeneration to loss of PARG activity. We found that loss of function of PARP genes pme-1 and pme-2 increased axon regeneration. Therefore, PARPs inhibit axon regeneration. Together with our PARG findings, these data suggest that levels of poly(ADP-ribose) are a critical determinant of regenerative potential.
Next, we investigated whether we could inhibit PARP activity post-injury to promote regeneration of damaged axons. Multiple PARP inhibitors are currently in clinical trials for indications including cancer and stroke. We tested whether PARP inhibitors could enhance axon regeneration. Wild type animals treated with chemical PARP inhibitors after injury showed significantly enhanced axon regeneration compared to controls. Thus, PARP activity regulates the acute response of neurons to axon injury, and PARP inhibition after injury is sufficient to improve regeneration. Together, our findings identify a novel pathway involving control of poly(ADP-ribose) levels that regulates axon regeneration.
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