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

Heng Li,Wen Li,Liumin He,Carolin Ruven,Xiaoli Wu,Bradley T Lang,Wutian Wu,Jerry Silver,Connie Wong

doi:10.1038/srep14923

Abstract

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 PTPσ. Previously, a small peptide memetic of the PTPσ wedge region named ISP (Intracellular Sigma Peptide) was generated, and its capabilities to target PTPσ and relieve CSPG inhibition were validated. Here, we demonstrate that after ventral root avulsion and immediate re-implantation, modulation of PTPσ 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 PTPσ is a potential therapeutic strategy for root avulsion.

Highlights

Following root avulsion, spinal nerves are physically disconnected from the spinal cord
We proposed that systemic manipulation of protein tyrosine phosphatase-σ (PTPσ) by ISP15 could help axons navigate through scar tissue in the central nervous system (CNS)-peripheral nervous system (PNS) transitional zone (TZ) and promote functional restoration after avulsion injury
Averaged Terzis grooming test (TGT) scores were remarkably increased by ISP treatment, and significant differences were observed at 3, 6- and 7-weeks post surgery

Summary

Introduction

Spinal nerves are physically disconnected from the spinal cord. There is rampant death of injured neurons, degeneration of axons, scar formation in the spinal cord and loss of synapses, which result in disability of distal muscles and diminution of sensorimotor functions[1,3,4]. In order to restore motor function after avulsion, injured motoneurons must survive and regenerate axons, which need to elongate through inhibitory scar tissue in the TZ before re-entering into the peripheral nerve trunk and eventually form synapses with distal target muscles[1,4]. Recent studies have shown that modulation of PTPσ could relieve axonal inhibition by CSPGs and enhance functional recovery after spinal cord injury[15] and ischemic heart attack[16]. Knockout of PTPσ accelerated axon extension and promoted functional recovery after peripheral nerve injury[20]

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Results

Conclusion