Department of Genetics, Yale University School of Medicine, New Haven, United States; Department of Neuroscience, Yale University School of Medicine, New Haven, United States; Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, United States
Rebecca D McWhirter
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, United States; Program in Neuroscience, Vanderbilt University, Nashville, United States
Yuichi Sekine
Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, United States; Department of Neurology, Yale University School of Medicine, New Haven, United States
Department of Neuroscience, Yale University School of Medicine, New Haven, United States; Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, United States; Department of Neurology, Yale University School of Medicine, New Haven, United States
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, United States; Program in Neuroscience, Vanderbilt University, Nashville, United States
Department of Genetics, Yale University School of Medicine, New Haven, United States; Department of Neuroscience, Yale University School of Medicine, New Haven, United States; Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, United States
The ability of a neuron to regenerate its axon after injury depends in part on its intrinsic regenerative potential. Here, we identify novel intrinsic regulators of axon regeneration: poly(ADP-ribose) glycohodrolases (PARGs) and poly(ADP-ribose) polymerases (PARPs). PARGs, which remove poly(ADP-ribose) from proteins, act in injured C. elegans GABA motor neurons to enhance axon regeneration. PARG expression is regulated by DLK signaling, and PARGs mediate DLK function in enhancing axon regeneration. Conversely, PARPs, which add poly(ADP-ribose) to proteins, inhibit axon regeneration of both C. elegans GABA neurons and mammalian cortical neurons. Furthermore, chemical PARP inhibitors improve axon regeneration when administered after injury. Our results indicate that regulation of poly(ADP-ribose) levels is a critical function of the DLK regeneration pathway, that poly-(ADP ribosylation) inhibits axon regeneration across species, and that chemical inhibition of PARPs can elicit axon regeneration.
