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Volume 17, Number 16, Issue of August 15, 1997 pp. 6165-6178
Copyright ©1997 Society for Neuroscience

Establishment of a Cell-Free System of Neuronal Apoptosis: Comparison of Premitochondrial, Mitochondrial, and Postmitochondrial Phases

Received March 17, 1997; revised May 9, 1997; accepted May 23, 1997.

H. Michael Ellerby1, Seamus J. Martin2, Lisa M. Ellerby1, Shahrouz S. Naiem1, 6, Shahrooz Rabizadeh1, 7, Guy S. Salvesen1, Carlos A. Casiano3, Neil R. Cashman4, Douglas R. Green5, and Dale E. Bredesen1, 7

1 The Burnham Institute, La Jolla Cancer Research Center, La Jolla, California 92037, 2 Molecular Cell Biology Laboratory, Maynooth University College, County Kildare, Ireland, 3 Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, 4 Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4, 5 La Jolla Institute for Allergy and Immunology, San Diego, California 92121, 6 Program in Molecular Pathology, University of California, San Diego, California 92093, and 7 Interdepartmental Program in Neuroscience, University of California, Los Angeles, California 90024

Apoptosis is a fundamental process required for normal development of the nervous system and is triggered during neurodegenerative disease. To dissect the molecular events leading to neuronal cell death, we have developed a cell-free model of neuronal apoptosis. The model faithfully reproduces key elements of apoptosis, including chromatin condensation, DNA fragmentation, caspase activation/processing, and selective substrate cleavage. We report that cell-free apoptosis is activated in premitochondrial, mitochondrial, and postmitochondrial phases by tamoxifen, mastoparan, and cytochrome c, respectively, allowing a functional ordering of these proapoptotic modulators. Furthermore, this is the first report of mitochondrial-mediated activation of cell-free apoptosis in a cell extract. Although Bcl-2 blocks activation at the premitochondrial and mitochondrial levels, it does not affect the postmitochondrial level. The cell-free system described here provides a valuable tool to elucidate the molecular events leading to neuronal cell death.

Key words: caspase; protease; apoptosis; cell-free; mitochondria; mastoparan; neuronal




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