tPA promotes ADAMTS-4-induced CSPG degradation, thereby enhancing neuroplasticity following spinal cord injury

• Main Authors: Sighild Lemarchant, Mathilde Pruvost, Marie Hébert, Maxime Gauberti, Yannick Hommet, Aurélien Briens, Eric Maubert, Yatma Gueye, François Féron, Didier Petite, Marcel Mersel, Jean-Claude do Rego, Hubert Vaudry, Jari Koistinaho, Carine Ali, Véronique Agin, Evelyne Emery, Denis Vivien
• Format: Article
• Language: English
• Published: Elsevier 2014-06-01
• Series: Neurobiology of Disease
• Subjects: Type 4 disintegrin and metalloproteinase with thrombospondin motifs; Tissue plasminogen activator; Spinal cord injury; Chondroitin sulfate proteoglycans; Neurocan; Neuroplasticity
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996114000473

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.