Enhanced regeneration and functional recovery after spinal root avulsion by manipulation of the proteoglycan receptor PTPσ

Following root avulsion, spinal nerves are physically disconnected from the spinal cord. Severe motoneuron death and inefficient axon regeneration often result in devastating motor dysfunction. Newly formed axons need to extend through inhibitory scar tissue at the CNS-PNS transitional zone before entering into a pro-regenerative peripheral nerve trajectory. CSPGs are dominant suppressors in scar tissue and exert inhibition via neuronal receptors including PTP sigma. Previously, a small peptide memetic of the PTP sigma wedge region named ISP (Intracellular Sigma Peptide) was generated, and its capabilities to target PTP sigma and relieve CSPG inhibition were validated. Here, we demonstrate that after ventral root avulsion and immediate re-implantation, modulation of PTP sigma by systemic delivery of ISP remarkably enhanced regeneration. ISP treatment reduced motoneuron death, increased the number of axons regenerating across scar tissue, rebuilt healthy neuromuscular junctions and enhanced motor functional recovery. Our study shows that modulation of PTP sigma is a potential therapeutic strategy for root avulsion.