The human neural circuit is about 50 thousand kilometers in length which is connected by axons. During development of the neuronal network, neurons connect with one another by extending their axons. The longest axon in human can stretch up to approximately 1 meter.
The delicate neural circuit can be easily disrupted by physical forces. For example, spinal cord injury can cause a series of damage to the neuronal axons. Distal part of neurons undergo Wallerian degeneration and removed from tissue, while proximal part of neurons are still alive and try to extend their axons again to reconnect neural circuits. However, their efforts end up in vein. As a result, neural network permanently remains disconnected and patients suffer from paralysis for life. One of the reasons is the accumulation of chondroitin sulfate (CS) at the injury site. In contrast, heparan sulfate (HS) promotes axon growth. Interestingly, HS and CS are similar in molecular structure and bind to the same receptor, PTPRσ (a receptor type tyrosine protein phosphatase). However, it has been elusive why or how these similar glycans cause opposite effects on the axon regeneration through the same receptor.
Based on chemically synthesized a series of HS and CS, which are different both in length and sulfation patterns. We found that HS could polymerize PTPRσ and promote axonal extension, while CS monomerized it and disrupted the extension. Upon binding to PTPRσ, CS activated this receptor’s enzymatic activity, and consequently dephosphorylated cortactin. As cortactin is critical for autophagy, CS-induced cortactin de-phosphorylation stopped autophagy flux and transformed axon tips to ball-like structures, so-called dystrophic endballs, the hallmark of injured axon. Indeed, an artificial disruption of autophagy induced dystrophic endballs.
Taken together, our results clearly revealed novel CS-PTPRσ-Cortactin-autophagy pathway which was involved in axonal regeneration inhibition.