Isolation of Short Peptides to Neutralize the Inhibitory Effect of Chondroitin Sulfate Proteoglycans

Neuronal damage due to spinal cord and brain injury can result in paralysis and/or loss of sensory function. A major contribution to loss of function is the inability of central nervous system neurons to regenerate to their original targets. One factor that confounds regeneration is the injury-induced upregulation of inhibitory proteoglycans (PGs), especially chondroitin sulfate proteoglycans (CSPGs). The majority ofCSPGs produced after injury originate from reactive astrocytes surrounding the lesion site. CSPGs interact and prevent the growth of regenerating axons by as of yet an unknown mechanism; however, glycosaminoglycan side chains attached to the protein core are considered the responsible agent. This has been further demonstrated in a number of experiments in which the digestion of chondroitin sulfate has increased regeneration. This process eliminates all of the chondroitin from the protein core but does not identify the mechanism by which these complex sugars inhibit axonal growth. Chondroitin sulfate is composed of repeating disaccharides that can be sulfated in a number of different locations. The sulfation pattern of the disaccharide is thought to alter the characteristics of the sugar and its function. To better elucidate how these different disaccharide sulfation patterns affect axonal growth, we are isolating a series of short peptides that bind to chondroitin. This study seeks to characterize these and other peptide sequences in order to identify and isolate peptides that specifically bind the sulfated forms of the disaccharide most commonly found in CSPG in the injured brain. Generation of binding peptides to these disaccharides might be useful in neutralizing the chondroitin interactions that inhibits axonal regeneration. Identification of the CSPG binding peptides could lead to the development of therapeutic strategies to ensure the regeneration of injured neurons to their appropriate targets and to restore compromised neuronal circuitry and function following spinal cord and/or brain injury.