Peptide inhibitors of LAR family phosphatases release CSPG mediated entrapment of axons and promote robust behavioral recovery following contusive spinal cord injury.

This cutting edge progressive scientific research project being undertaken by Dr. Jerry Silver at Case Western Reserve University and his collaborative team are now moving into chronic spinal cord injury models. This is a project being supported by UNITE 2 FIGHT PARALYSIS and the CURE WARRIORS to devise a therapy for chronic spinal cord injury. Dr. Silver will be presenting information about these remarkable studies and his teams efforts in addition to answering questions at the Working 2 Walk Science and Advocacy Symposium in Irvine, California on November 1 -2, 2012.

Program#/Poster#: 252.07/M6
Location: Hall F-J Neuroscience 2012, SfN’s 42nd annual meeting, is scheduled for Oct. 13 -17 in New Orleans at the Ernest N. Morial Convention Center.
Presentation time: Sunday, Oct 14, 2012, 3:00 PM – 4:00 PM
Authors: *B. T. LANG1, J. M. CREGG1, M. A. DEPAUL1, A. R. FILOUS1, T. A. EVANS1, Y. L. WENG1, A. Y. HUANG2, S. LI3, J. SILVER1;
1Dept. of Neurosciences, 2Dept. of Pediatrics, Case Western Reserve Univ., Cleveland, OH; 3Neurol. and Neurosci. Grad. Program, Univ. of Texas Southwestern Med. Ctr., Dallas, TX

Abstract: Regeneration following spinal cord injury is curtailed by several processes, with the inhibitory chondroitin-sulfate proteoglycan (CSPG) rich glial scar being the primary impediment. Recent reports have identified the pro-synaptic proteins, Protein Tyrosine Phosphatase-Sigma (PTPσ) and Leukocyte common Antigen-Related (LAR) as the first CSPG receptors, although it is currently unknown how these receptors function to prevent axonal regeneration. Using an in vitro assay of the glial scar and time-lapse microscopy, we show that long-term exposure to gradients of CSPGs causes growth cones to stabilize and over-adhere within the CSPG substrate. Immunohistochemical analyses showed that PTPσ and LAR become highly concentrated in the terminally stabilized growth cones. A small membrane penetrating peptide inhibitor of the intracellular domain of LAR or a similar novel peptide inhibitor of PTPσ added to the cultures prevented the stabilization and over-adhesion of growth cones and allowed motility even after the longest exposure to CSPG. Furthermore, peptide treatment could reactivate growth cones into a highly motile state even after stabilization. One day following spinal cord injuries inflicted via an Infinite Horizon device, we administered long-term daily subcutaneous injections of each peptide, a combination of both or a vehicle control. Inactivation of RPTPσ, but not LAR, following severe contusive spinal cord injury allowed for remarkable recovery of hindlimb function, locomotor activity, and bladder control. Our results suggest for the first time that CSPGs in the lesion environment block regenerative growth by creating an abnormally high adhesive interaction between the substrate and the dystrophic axon. Furthermore, we show that LAR and PTPσ can be modulated and inactivated to prevent the over-adhesion and stabilization of axons following spinal cord injury. Most importantly, inactivation of PTPσ with a novel, easily injectable, small peptide inhibitor allowed unprecedented levels of functional recovery following spinal cord injury, presenting a potential new avenue of treatment for paralysis.

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