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© The Rockefeller University Press, 0021-9525/2000//131 $5.00
The Journal of Cell Biology, Volume 150, Number 1, , 2000 131-144

Caspase Inhibition Extends the Commitment to Neuronal Death Beyond Cytochrome c Release to the Point of Mitochondrial Depolarization

^a Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110
^b Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110
^c Vertex Pharmaceutical, Cambridge, Massachusetts 02139
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110.(314) 747-1772(314) 362-3926

ejohnson{at}pcg.wustl.edu

Nerve growth factor (NGF) deprivation induces a Bax-dependent, caspase-dependent programmed cell death in sympathetic neurons. We examined whether the release of cytochrome c was accompanied by the loss of mitochondrial membrane potential during sympathetic neuronal death. NGF- deprived, caspase inhibitor–treated mouse sympathetic neurons maintained mitochondrial membrane poten-tial for 25–30 h after releasing cytochrome c. NGF- deprived sympathetic neurons became committed to die, as measured by the inability of cells to be rescued by NGF readdition, at the time of cytochrome c release. In the presence of caspase inhibitor, however, this commitment to death was extended beyond the point of cytochrome c release, but only up to the subsequent point of mitochondrial membrane potential loss. Caspase-9 deficiency also arrested NGF-deprived sympathetic neurons after release of cytochrome c, and permitted these neurons to be rescued with NGF readdition. Commitment to death in the NGF-deprived, caspase- 9–deficient sympathetic neurons was also coincident with the loss of mitochondrial membrane potential. Thus, caspase inhibition extended commitment to death in trophic factor–deprived sympathetic neurons and allowed recovery of neurons arrested after the loss of cytochrome c, but not beyond the subsequent loss of mitochondrial membrane potential.

Key Words: apoptosis • caspase-9 • bax • sympathetic neurons • NGF

© 2000 The Rockefeller University Press

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