FAS deficiency reduces apoptosis, spares axons and improves function after spinal cord injury.
After spinal cord injury (SCI), apoptosis of neurons and oligodendrocytes is associated with axonal degeneration and loss of neurological function. Recent data have suggested a potential role for FAS death receptor-mediated apoptosis in the pathophysiology of SCI. In this study, we examined the effect of FAS deficiency on SCI in vitro and in vivo. FAS(Lpr/lpr) mutant mice and wildtype background-matched mice were subjected to a T5-6 clip compression SCI, and complementary studies were done in an organotypic slice culture model of SCI. Post-traumatic apoptosis in the spinal cord, which was seen in neurons and oligodendrocytes, was decreased in the FAS-deficient mice both in vivo and in vitro particularly in oligodendrocytes. FAS deficiency was also associated with improved locomotor recovery, axonal sparing and preservation of oligodendrocytes and myelin. However, FAS deficiency did not result in a significant increase in surviving neurons in the spinal cord at 6 weeks after injury, likely reflecting the importance of other cell death mechanisms for neurons. We conclude that inhibition of the FAS pathway may be a clinically attractive neuroprotective strategy directed towards oligodendroglial and axonal preservation in the treatment of SCI and neurotrauma.
Casha
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Spinal Program, Krembil Neuroscience Center, Toronto Western Hospital, 399 Bathurst St., Toronto, Ontario, Canada M5T 2S8.
Yu
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Fehlings
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D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001369:Axons / Q000502:physiology*; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D004195:Disease Models, Animal; D005260:Female; D007839:Functional Laterality; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D020287:In Situ Nick-End Labeling / Q000379:methods; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology*; D009124:Muscle Proteins / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011419:Propidium; D020127:Recovery of Function / Q000235:genetics*; D013119:Spinal Cord Injuries / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D013266:Stilbamidines / Q000378:metabolism; D013997:Time Factors; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D005904:Glial Fibrillary Acidic Protein; D006360:Heat-Shock Proteins; D007211:Indoles; D009124:Muscle Proteins; D013266:Stilbamidines; D019014:fas Receptor; C483911:p20 protein, mouse; C018588:Luxol Fast Blue MBS; D011419:Propidium; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases; D010751:Phosphopyruvate Hydratase