Axonal regrowth after spinal cord injury via chondroitinase and the tissue plasminogen activator (tPA)/plasmin system.

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2011-10

Authors

Bukhari, Noreen
Torres, Luisa
Robinson, John K
Tsirka, Stella E

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Abstract

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.

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Axons, Animals, Mice, Inbred C57BL, Mice, Knockout, Mice, Spinal Cord Injuries, Disease Models, Animal, Glial Fibrillary Acidic Protein, Microfilament Proteins, Chondroitinases and Chondroitin Lyases, Tissue Plasminogen Activator, Chondroitin ABC Lyase, Proteoglycans, Calcium-Binding Proteins, Antigens, Laminectomy, Rotarod Performance Test, Exploratory Behavior, Motor Activity, Recovery of Function, Fibrinolysin, Chondroitin Sulfate Proteoglycans

Citation

Published Version (Please cite this version)

10.1523/jneurosci.3339-11.2011

Publication Info

Bukhari, Noreen, Luisa Torres, John K Robinson and Stella E Tsirka (2011). Axonal regrowth after spinal cord injury via chondroitinase and the tissue plasminogen activator (tPA)/plasmin system. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31(42). pp. 14931–14943. 10.1523/jneurosci.3339-11.2011 Retrieved from https://hdl.handle.net/10161/22506.

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Bukhari-Parlakturk

Noreen Bukhari-Parlakturk

Assistant Professor of Neurology

I have a long standing interest in developing disease-modifying therapies for movement disorders, a major unmet clinical need. I work at the interface of neuroscience and neurology to apply mechanistic understanding of neurological disease to develop targeted neuromodulatory therapies and in the process further disease mechanisms and medical therapy.


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