Non-invasive systemic modulation of the CSPG receptor PTPσ promotes locomotor and urinary recovery following severe contusive spinal cord injury
Authors: *B. T. LANG1, J. M. CREGG1, M. A. DEPAUL1, A. R. FILOUS1, A. P. TRAN1, S. LI2, T. A. EVANS1, S. A. BUSCH1, J. SILVER1;
1Dept. of Neurosciences, Case Western Reserve Univ., Cleveland, OH; 2Temple Univ. Sch. of Med., Shriners Hosp. Pediatric Res. Ctr. and Dept. of Anat. and Cell Biol., Philadelphia, PA
Abstract: Regeneration and sprouting following spinal cord injury is curtailed by several processes, with the inhibitory chondroitin-sulfate proteoglycan (CSPG)-rich glial scar and perineuronal net being major impediments. Recent reports have identified the pro-synaptic Protein Tyrosine Phosphatase-Sigma (PTPσ) as a CSPG receptor, although it is currently unknown how this receptor functions in regeneration failure. We previously showed that PTPσ becomes concentrated in dystrophic growth cones in vitro, leading to a loss of motility, over-adhesion, and ultimately entrapment. Using the sequence homology between PTPσ, LAR, and PTPu, we identified a highly conserved regulatory wedge within the intracellular D1 phosphatase domain of PTPσ. A novel membrane-permeable peptide mimetic of the PTPσ wedge (ISP) relieves CSPG mediated over-adhesion and loss of motility in vitro in a dose dependent manner. Spinal cord injury was induced with the infinite Horizon device at Thoracic level 8-9 (250kD). This severe contusive injury results in a near total loss of hind limb weight-bearing and coordination. Micturition is also strongly disrupted. One day following spinal cord injury, we began administering daily subcutaneous injections of ISP, other similar wedge peptides, or vehicle control. Peptide modulation of only PTPσ allowed for remarkable recovery of hindlimb function, locomotor activity, and bladder control in thirteen of fifteen animals by twelve weeks post injury. On average, ISP treatment improved BBB scores of responding animals (50% respond) from occasional stepping (BBB=10) to consistent coordination locomotion with frequent toe clearance (BBB=16), with four animals regaining near normal locomotion (BBB>17). Further, peptide treatment led to a 50% decrease in the number of foot-faults on a gridwalk test. In addition, bladder function was significantly improved in 11 of 15 treated animals, with 4 animals regaining normal urination frequency. Anatomically, the behavioral recovery in treated animals correlated with a remarkably increased and unusually patterned 5HT expression multiple segments below the lesion. The unusual 5HT expression pattern suggests sprouting and/or regeneration to spared motor systems. No difference was seen in lesion volume or cortical spinal tract regeneration. Our results identify the CSPG receptor PTPσ as a primary regulator of regeneration/sprouting failure following spinal cord injury. Finally, we show that a cell-permeable wedge domain mimetic of PTPσ allows neurons to overcome CSPG mediated inhibition and promotes remarkable functional recovery following severe spinal cord injury.
Disclosures: B.T. Lang: None. J.M. Cregg: None. M.A. Depaul: None. A.R. Filous: None. A.P. Tran: None. S. Li: None. T.A. Evans: None. S.A. Busch: None. J. Silver: None.
Support: NINDS NS25713