Axonal regrowth after spinal cord injury via chondroitinase and the tissue plasminogen activator (tPA)/plasmin system.
Spinal cord injury (SCI) causes permanent debilitation due to the inability of axons to grow through established scars. Both the sugar chains and core proteins of chondroitin sulfate proteoglycans (CSPGs) are inhibitory for neurite regrowth. Chondroitinase ABC (ChABC) degrades the sugar chains and allows for synaptic plasticity, suggesting that after the sugar chain cleavage additional steps occur promoting a permissive microenvironment in the glial scar region. We report that the clearance of the core protein by the tissue plasminogen activator (tPA)/plasmin proteolytic system partially contributes to ChABC-promoted plasticity. tPA and plasmin are upregulated after SCI and degrade the deglycosylated CSPG proteins. Mice lacking tPA (tPA(-/-)) exhibit attenuated neurite outgrowth and blunted sensory and motor recovery despite ChABC treatment. Coadministration of ChABC and plasmin enhanced the tPA(-/-) phenotype and supported recovery in WT SCI mice. Collectively, these findings show that the tPA/plasmin cascade may act downstream of ChABC to allow for synergistic sensory and motor improvement compared with each treatment alone and suggest a potential new approach to enhance functional recovery after SCI.
Department of Pharmacological Sciences, Stony Brook University, New York, NY 11794-8651, USA.
Noreen
N
Bukhari
Luisa
L
Torres
John K
JK
Robinson
Stella E
SE
Tsirka
D000818:Animals; D000941:Antigens / Q000378:metabolism; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D019765:Chondroitin ABC Lyase / Q000494:pharmacology; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D002810:Chondroitinases and Chondroitin Lyases / Q000378:metabolism*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005341:Fibrinolysin / Q000378:metabolism* / Q000627:therapeutic use; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007796:Laminectomy / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D011509:Proteoglycans / Q000378:metabolism; D020127:Recovery of Function; D045442:Rotarod Performance Test; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology*; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000502:physiology*; D000099216:Chondroitin Sulfate Proteoglycan 4
D000941:Antigens; D002135:Calcium-Binding Proteins; D019765:Chondroitin ABC Lyase; D011508:Chondroitin Sulfate Proteoglycans; D002810:Chondroitinases and Chondroitin Lyases; D005341:Fibrinolysin; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D011509:Proteoglycans; D010959:Tissue Plasminogen Activator; D000099216:Chondroitin Sulfate Proteoglycan 4; C491049:Aif1 protein, mouse