PTPσ Is a Receptor for Chondroitin Sulfate Proteoglycan, an Inhibitor of Neural Regeneration

Science, 2009 · DOI: 10.1126/science.1178310 · Published: October 23, 2009

Simple Explanation

Recovery after central nervous system (CNS) injury is minimal, leading to substantial current interest in potential strategies to overcome this challenge. Chondroitin sulfate proteoglycans (CSPGs) show dramatic up-regulation after neural injury, within the extracellular matrix of scar tissue and in the perineuronal net within more-distant targets of the severed axons. The inhibitory nature of CSPGs is reflected not only in the formation of dystrophic axonal retraction bulbs that fail to regenerate through the lesion, but also in the limited capacity for collateral sprouting of spared fibers. This inhibition can be relieved by chondroitinase ABC digestion of the chondroitin sulfate (CS) side chains, which can promote regeneration and sprouting and restore lost function. The CSPGs and HSPGs are analogous structurally, both consisting of a core protein bearing negatively charged sulfated carbohydrate side chains. To test for binding, we used PTPσ together with neurocan/CSPG3, a major CSPG that is produced by reactive astroglia after CNS injury

Study Duration

Not specified

Participants

Mice, DRG neurons, C8-D1A astrocytes

Evidence Level

In vitro and in vivo experiments

Key Findings

1
PTPσ binds with high affinity to neural CSPGs. Binding involves the chondroitin sulfate chains and a specific site on the first immunoglobulin-like domain of PTPσ.
2
In culture, PTPσ−/− neurons show reduced inhibition by CSPG, showing a functional involvement of PTPσ in the response of young DRG neurons to inhibitory CSPGs.
3
After spinal cord injury, PTPσ gene disruption enhanced the ability of axons to penetrate regions containing CSPG. The results in this regeneration model system demonstrate a role for PTPσ in mediating the axonal response to the inhibitory CSPG-rich scar in a spinal cord lesion in vivo.

Research Summary

Chondroitin sulfate proteoglycans (CSPGs) present a barrier to axon regeneration. However, no specific receptor for the inhibitory effect of CSPGs has been identified. We showed that a transmembrane protein tyrosine phosphatase, PTPσ, binds with high affinity to neural CSPGs. In culture, PTPσ−/− neurons show reduced inhibition by CSPG. A PTPσ fusion protein probe can detect cognate ligands that are up-regulated specifically at neural lesion sites. After spinal cord injury, PTPσ gene disruption enhanced the ability of axons to penetrate regions containing CSPG. These results indicate that PTPσ can act as a receptor for CSPGs and may provide new therapeutic approaches to neural regeneration.

Practical Implications

Therapeutic Approaches

PTPσ as a receptor for CSPGs opens new therapeutic avenues for neural regeneration after injury.

Drug Design

The identification of the CSPG binding site on PTPσ provides a target for drug design to treat spinal cord injury.

Injury Biomarker

PTPσ fusion protein can detect lesion sites in the adult CNS and serves as a potential injury biomarker for research or diagnosis.

Study Limitations

1
The observation of some remaining inhibitory effect of CSPGs on PTPσ−/− neurons suggests the possible presence of additional receptors, which could be other PTPs in the LAR family or receptors in other families, or there could be additional receptor-independent mechanisms.
2
Robust regeneration beyond the core of the lesion did not occur. This might, in principle, reflect partial redundancy with other PTPs in the LAR subfamily, and it would also be consistent with the known presence of other growth impediments such as the myelin inhibitors and factors intrinsic to unconditioned neurons.
3
PTPσ also binds HSPGs and, potentially, other ligands

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