title: 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.
authors.affiliation: The Burke Medical Research Institute, White Plains, NY 10605; Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065 bcl2002@med.cornell.edu cab2026@med.cornell.edu.
authors.forename: Camille
authors.initials: C
authors.lastname: Brochier
authors.affiliation: The Burke Medical Research Institute, White Plains, NY 10605;
authors.forename: James I
authors.initials: JI
authors.lastname: Jones
authors.affiliation: The Burke Medical Research Institute, White Plains, NY 10605; Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065.
authors.forename: Dianna E
authors.initials: DE
authors.lastname: Willis
authors.affiliation: The Burke Medical Research Institute, White Plains, NY 10605; Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065 bcl2002@med.cornell.edu cab2026@med.cornell.edu.
authors.forename: Brett
authors.initials: B
authors.lastname: Langley
mesh_terms: D001369:Axons; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D009416:Nerve Regeneration; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: PAR; PARP1; axon; poly(ADP-ribose) polymerase; regeneration