Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury

Regeneration and plasticity after spinal cord injury are limited by inhibitory proteoglycans; here, modulation of a receptor for proteoglycans in rats is shown to lead to functional recovery after injury. Functional recovery following severe spinal cord injury is often modest due to inhibited neural and axonal regeneration at the scar location. Glia-produced extracellular matrix components may be responsible for this reduced regeneration potential. Using an in vitro model of the inhibitory extracellular matrix that forms after spinal cord injury, Jerry Silver and colleagues identify a component on axons — protein tyrosine phosphatase σ (PTPσ) — that permanently adheres axonal growth cones to these inhibitory extracellular matrix molecules, rendering the axons unable to regrow. In rodent model studies, a peptide mimic of PTPσ can block the proteoglycan sites in the matrix, allowing axons to pass through the injured area and regrow, leading to functional recovery in both the locomotor and urinary systems. Contusive spinal cord injury leads to a variety of disabilities owing to limited neuronal regeneration and functional plasticity. It is well established that an upregulation of glial-derived chondroitin sulphate proteoglycans (CSPGs) within the glial scar and perineuronal net creates a barrier to axonal regrowth and sprouting1,2,3,4,5. Protein tyrosine phosphatase σ (PTPσ), along with its sister phosphatase leukocyte common antigen-related (LAR) and the nogo receptors 1 and 3 (NgR), have recently been identified as receptors for the inhibitory glycosylated side chains of CSPGs6,7,8. Here we find in rats that PTPσ has a critical role in converting growth cones into a dystrophic state by tightly stabilizing them within CSPG-rich substrates. We generated a membrane-permeable peptide mimetic of the PTPσ wedge domain that binds to PTPσ and relieves CSPG-mediated inhibition. Systemic delivery of this peptide over weeks restored substantial serotonergic innervation to the spinal cord below the level of injury and facilitated functional recovery of both locomotor and urinary systems. Our results add a new layer of understanding to the critical role of PTPσ in mediating the growth-inhibited state of neurons due to CSPGs within the injured adult spinal cord.