PGC-1α Inhibits Schwann Cell Dedifferentiation and Delays Peripheral Nerve Degeneration by Targeting PON1

PPARγ coactivator-1 alpha (PGC-1α) is an essential transcription factor co-activator that regulates gene transcription and neural regeneration. Schwann cells, which are unique glial cells in peripheral nerves that dedifferentiate after peripheral nerve injury (PNI) and are released from degenerative nerves. Wallerian degeneration is a series of stereotypical events that occurs in response to nerve fibers after PNI. The role of PGC-1α in Schwann cell dedifferentiation and Wallerian degeneration is not yet clear. As Wallerian degeneration plays a crucial role in PNI, we conducted a study to determine whether PGC-1α has an effect on peripheral nerve degeneration after injury. We examined the expression of PGC-1α after sciatic nerve crush or transection using Western blotting and found that PGC-1α expression increased after PNI. Then we utilized ex vivo and in vitro models to investigate the effects of PGC-1α inhibition and activation on Schwann cell dedifferentiation and nerve degeneration. Our findings indicate that PGC-1α negatively regulates Schwann cell dedifferentiation and nerve degeneration. Through the use of RNA-seq, siRNA/plasmid transfection and reversal experiments, we identified that PGC-1α targets inhibit the expression of paraoxonase 1 (PON1) during Schwann cell dedifferentiation in degenerated nerves. In summary, PGC-1α plays a crucial role in preventing Schwann cell dedifferentiation and its activation can reduce peripheral nerve degeneration by targeting PON1. Graphical Abstract PGC-1α inhibits Schwann cell dedifferentiation and peripheral nerve degeneration. PGC-1α negatively regulates Schwann cell dedifferentiation and peripheral nerve degeneration after injury by targeting PON1.