title: tPA promotes ADAMTS-4-induced CSPG degradation, thereby enhancing neuroplasticity following spinal cord injury.
abstract: Although tissue plasminogen activator (tPA) is known to promote neuronal remodeling in the CNS, no mechanism of how this plastic function takes place has been reported so far. We provide here in vitro and in vivo demonstrations that this serine protease neutralizes inhibitory chondroitin sulfate proteoglycans (CSPGs) by promoting their degradation via the direct activation of endogenous type 4 disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-4). Accordingly, in a model of compression-induced spinal cord injury (SCI) in rats, we found that administration of either tPA or its downstream effector ADAMTS-4 restores the tPA-dependent activity lost after the SCI and thereby, reduces content of CSPGs in the spinal cord, a cascade of events leading to an improved axonal regeneration/sprouting and eventually long term functional recovery. This is the first study to reveal a tPA-ADAMTS-4 axis and its function in the CNS. It also raises the prospect of exploiting such cooperation as a therapeutic tool for enhancing recovery after acute CNS injuries.
authors.affiliation: Inserm UMR-S 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, University of Caen Basse-Normandie, GIP CYCERON, F-14074 Caen Cedex, France.
authors.forename: Sighild
authors.initials: S
authors.lastname: Lemarchant
authors.affiliation: Inserm UMR-S 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, University of Caen Basse-Normandie, GIP CYCERON, F-14074 Caen Cedex, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Pruvost
authors.affiliation: Inserm UMR-S 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, University of Caen Basse-Normandie, GIP CYCERON, F-14074 Caen Cedex, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Hébert
authors.affiliation: Inserm UMR-S 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, University of Caen Basse-Normandie, GIP CYCERON, F-14074 Caen Cedex, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Gauberti
authors.affiliation: Inserm UMR-S 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, University of Caen Basse-Normandie, GIP CYCERON, F-14074 Caen Cedex, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Hommet
authors.affiliation: Inserm UMR-S 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, University of Caen Basse-Normandie, GIP CYCERON, F-14074 Caen Cedex, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Briens
authors.affiliation: Inserm UMR-S 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, University of Caen Basse-Normandie, GIP CYCERON, F-14074 Caen Cedex, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Maubert
authors.affiliation: CNRS UMR-6184, Neurobiologie des Interactions Cellulaires et Neurophysiopathologie, IFR Jean Roche, Faculté de Médecine, University of Aix-Marseille, F-13916 Marseille, France.
authors.forename: Yatma
authors.initials: Y
authors.lastname: Gueye
authors.affiliation: CNRS UMR-6184, Neurobiologie des Interactions Cellulaires et Neurophysiopathologie, IFR Jean Roche, Faculté de Médecine, University of Aix-Marseille, F-13916 Marseille, France.
authors.forename: François
authors.initials: F
authors.lastname: Féron
authors.affiliation: Inserm UMR-S 583, Institute for Neurosciences of Montpellier, Pathophysiology and Therapy of Sensory and Motor Deficits, Saint Eloi Hospital, F-34091 Montpellier, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Petite
authors.affiliation: Inserm UMR-S 583, Institute for Neurosciences of Montpellier, Pathophysiology and Therapy of Sensory and Motor Deficits, Saint Eloi Hospital, F-34091 Montpellier, France.
authors.forename: Marcel
authors.initials: M
authors.lastname: Mersel
authors.affiliation: Inserm UMR-S 982, Différenciation et Communication Neuronale et Neuroendocrine, PRIMACEN, IFRMP 23, University of Rouen, F-76130 Mont-Saint-Aignan, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: do Rego
authors.affiliation: Inserm UMR-S 982, Différenciation et Communication Neuronale et Neuroendocrine, PRIMACEN, IFRMP 23, University of Rouen, F-76130 Mont-Saint-Aignan, France.
authors.forename: Hubert
authors.initials: H
authors.lastname: Vaudry
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Koistinaho
authors.affiliation: Inserm UMR-S 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, University of Caen Basse-Normandie, GIP CYCERON, F-14074 Caen Cedex, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Ali
authors.affiliation: Inserm UMR-S 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, University of Caen Basse-Normandie, GIP CYCERON, F-14074 Caen Cedex, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Agin
authors.affiliation: Inserm UMR-S 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, University of Caen Basse-Normandie, GIP CYCERON, F-14074 Caen Cedex, France; Department of Neurosurgery, Caen University Hospital, Avenue de la Côte de Nacre, F-14000 Caen, France. Electronic address: emery-e@chu-caen.fr.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Emery
authors.affiliation: Inserm UMR-S 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, University of Caen Basse-Normandie, GIP CYCERON, F-14074 Caen Cedex, France. Electronic address: vivien@cyceron.fr.
authors.forename: Denis
authors.initials: D
authors.lastname: Vivien
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000071121:ADAMTS4 Protein; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism*; D005260:Female; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D058580:Neurocan; D009473:Neuronal Plasticity / Q000187:drug effects*; D009479:Neuropeptides / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology; D011348:Procollagen N-Endopeptidase / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D015843:Serpins / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D013117:Spinal Cord Compression / Q000188:drug therapy / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000503:physiopathology; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000097522:Neuroserpin
chemical_list: D051722:ADAM Proteins; D000071121:ADAMTS4 Protein; D011508:Chondroitin Sulfate Proteoglycans; D058580:Neurocan; D009479:Neuropeptides; D018696:Neuroprotective Agents; D017395:Plasminogen Activator Inhibitor 1; D011348:Procollagen N-Endopeptidase; D015842:Serine Proteinase Inhibitors; D015843:Serpins; D010959:Tissue Plasminogen Activator; D000097522:Neuroserpin; C539091:Ncan protein, rat
keywords: Chondroitin sulfate proteoglycans; Neurite growth; Neurocan; Neuroplasticity; Serotoninergic fibers; Spinal cord injury; Tissue plasminogen activator; Type 1 plasminogen activator inhibitor; Type 4 disintegrin and metalloproteinase with thrombospondin motifs