期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：49
页码：15220-15225
DOI：10.1073/pnas.1509754112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceDamage to axons in the central nervous system typically results in permanent functional deficits; however, the regenerative capacity of injured neurons can be improved by blocking signals from damaged myelin and activated astrocytes, which act as molecular and physical barriers to regeneration. Here, we identify poly(ADP-ribose) polymerase 1 (PARP1) as a previously unidentified and critical mediator of axon growth inhibition. We show that exposure of neurons to diverse growth-inhibiting molecules activates PARP1, resulting in the accumulation of poly(ADP-ribose) in the cell body and axon and limited axonal growth. Accordingly, the pharmacological inhibition or genetic loss of PARP1 markedly facilitates axon regeneration. Together, our findings provide critical insights into mechanisms of axon growth and identify PARP1 as a potent target to reverse neurological disability. 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.
关键词：poly(ADP-ribose) polymerase ; PARP1 ; PAR ; axon ; regeneration
