title: Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury.
abstract: Contusive spinal cord injury leads to a variety of disabilities owing to limited neuronal regeneration and functional plasticity. It is well established that an upregulation of glial-derived chondroitin sulphate proteoglycans (CSPGs) within the glial scar and perineuronal net creates a barrier to axonal regrowth and sprouting. Protein tyrosine phosphatase σ (PTPσ), along with its sister phosphatase leukocyte common antigen-related (LAR) and the nogo receptors 1 and 3 (NgR), have recently been identified as receptors for the inhibitory glycosylated side chains of CSPGs. Here we find in rats that PTPσ has a critical role in converting growth cones into a dystrophic state by tightly stabilizing them within CSPG-rich substrates. We generated a membrane-permeable peptide mimetic of the PTPσ wedge domain that binds to PTPσ and relieves CSPG-mediated inhibition. Systemic delivery of this peptide over weeks restored substantial serotonergic innervation to the spinal cord below the level of injury and facilitated functional recovery of both locomotor and urinary systems. Our results add a new layer of understanding to the critical role of PTPσ in mediating the growth-inhibited state of neurons due to CSPGs within the injured adult spinal cord.
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Lang
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Cregg
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Marc A
authors.initials: MA
authors.lastname: DePaul
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Amanda P
authors.initials: AP
authors.lastname: Tran
authors.affiliation: Center for Brain and Spinal Cord Repair, Department of Neuroscience, Wexner Medical Center at The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Kui
authors.initials: K
authors.lastname: Xu
authors.affiliation: Regenerative Medicine Program and Department of Physiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Dyck
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Madalena
authors.affiliation: Baldwin Wallace University, Berea, Ohio 44017, USA.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Brown
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA.
authors.forename: Yi-Lan
authors.initials: YL
authors.lastname: Weng
authors.affiliation: Shriners Hospital's Pediatric Research Center (Center for Neural Repair and Rehabilitation), Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Shuxin
authors.initials: S
authors.lastname: Li
authors.affiliation: Regenerative Medicine Program and Department of Physiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada.
authors.forename: Soheila
authors.initials: S
authors.lastname: Karimi-Abdolrezaee
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Busch
authors.affiliation: Center for Brain and Spinal Cord Repair, Department of Neuroscience, Wexner Medical Center at The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Silver
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism*; D005109:Extracellular Matrix / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D005260:Female; D020439:Growth Cones / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009416:Nerve Regeneration / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000473:pathology
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2