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The Journal of Neuroscience, September 15, 2000, 20(18):6879-6887

Fas Receptor and Neuronal Cell Death after Spinal Cord Ischemia

Kohji Matsushita¹, Yongqin Wu¹, Jianhua Qiu¹, Loic Lang-Lazdunski¹, Lorenz Hirt¹, Christian Waeber¹, Bradley T. Hyman², Junying Yuan³, and Michael A. Moskowitz¹

¹ Neuroscience Center and ² Alzheimer's Disease Research Unit, Massachusetts General Hospital, Harvard Medical School, and ³ Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02129

Cell death from spinal cord injury is mediated in part by apoptotic mechanisms involving downstream caspases (e.g., caspase-3). Upstream mechanisms may involve other caspases such as procaspase-8, a 55 kDa apical caspase, which we found constitutively expressed within spinal cord neurons along with Fas. As early as 1.5 hr after transient ischemia, activated caspase-8 (p18) and caspase-8 mRNA appeared within neurons in intermediate gray matter and in medial ventral horn. We also detected evidence for an increase in death receptor complex by co-immunoprecipitation using Fas and anti-procaspase-8 after ischemia. At early time points, Fas and p18 were co-expressed within individual neurons, as were activated caspase-8 and caspase-3. Moreover, we detected p18 in cells before procaspase-3 cleavage product (p20), suggesting sequential activation. The appearance of cytosolic cytochrome c and gelsolin cleavage after ischemia was consistent with mitochondrial release and caspase-3 activation, respectively. Numerous terminal deoxynucleotidyl transferase-mediated DNA nick end-labeling-positive neurons contained p18 or p20 (65 and 80%, respectively), thereby supporting the idea that cells undergoing cell death contain both processed caspases. Our data are consistent with the idea that transient spinal cord ischemia induces the formation of a death-inducing signaling complex, which may participate in caspase-8 activation and sequential caspase-3 cleavage. Death receptors as well as downstream caspases may be useful therapeutic targets for limiting the death of cells in spinal cord.

Key words: caspase-8; caspase-3; spinal cord ischemia; Fas; DISC; cell death

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20186879-09$05.00/0

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