Targeting proteoglycan receptor PTPσ restores sensory function after spinal cord dorsal root injury by activation of Erks/CREB signaling pathway

Abstract Dorsal root injury commonly results in irreversible loss of sensory functions because of the limited intrinsic regenerative capacity of adult sensory axons and the growth-inhibitory environment at the dorsal root entry zone (DREZ) between the dorsal root and the spinal cord. Chondroitin sulfate proteoglycans (CSPGs) are the dominant suppressors of axonal regeneration, acting via neuronal receptors including protein tyrosine phosphatase-σ (PTPσ). ISP (Intracellular Sigma Peptide) is a small peptide mimetic of the PTPσ wedge region that has been developed to target PTPσ and relieve CSPG inhibition. Extracellular regulated kinases (Erks) and cAMP response element binding protein (CREB) are signaling molecules downstream of CSPGs and PTPσ; they are expressed in neurons and essential for axon growth. In this study, we observed that ISP administration could promote sensory function restoration in adult rats after dorsal spinal root crush injury. Our results show that systemic ISP administration would not only significantly increase sensory axon regeneration and functional recovery, but also activate Erk and CREB signaling pathway. Furthermore, ISP has also been verified to increase dorsal root ganglion axonal remyelination in vitro . These results suggest that modulation of PTPσ by ISP represents a promising therapeutic strategy for sensory neuronal injuries.