PARP knockdown promotes synapse reformation after axon injury

Micah Y. Belew, Wenjia Huang, Jeremy T. Florman, Mark J. Alkema, Alexandra B. Byrne
2023 · doi:10.1101/2023.11.03.565562
preprint OA: closed
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Abstract

Injured nervous systems are often incapable of self-repairing, resulting in permanent loss of function and disability. To restore function, a severed axon must not only regenerate, but must also reform synapses with target cells. Together, these processes beget functional axon regeneration. Progress has been made towards a mechanistic understanding of axon regeneration. However, the molecular mechanisms that determine whether and how synapses are formed by a regenerated motor axon are not well understood. Using a combination of in vivo laser axotomy, genetics, and high-resolution imaging, we find that poly (ADP-ribose) polymerases (PARPs) inhibit synapse reformation in regenerating axons. As a result, regenerated parp(-) axons regain more function than regenerated wild-type axons, even though both have reached their target cells. We find that PARPs regulate both axon regeneration and synapse reformation in coordination with proteolytic calpain CLP-4. These results indicate approaches to functionally repair the injured nervous system must specifically target synapse reformation, in addition to other components of the injury response.

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