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The Journal of Neuroscience, February 15, 2000, 20(4):1333-1341
Evidence That Wallerian Degeneration and Localized Axon Degeneration Induced by Local Neurotrophin Deprivation Do Not Involve Caspases
John T. Finn1, Miguel Weil1, Fabienne Archer2, Robert Siman3, Anu Srinivasan4, and Martin C. Raff1 1 Medical Research Council Laboratory for Molecular Cell Biology and Biology Department and 2 Department of Physiology, University College London, London WC1E 6BT, United Kingdom, 3 Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084, and 4 Idun Pharmaceuticals, Inc., La Jolla, California 92037
The selective degeneration of an axon, without the death of the parent neuron, can occur in response to injury, in a variety of metabolic, toxic, and inflammatory disorders, and during normal development. Recent evidence suggests that some forms of axon degeneration involve an active and regulated program of self-destruction rather than a passive "wasting away" and in this respect and others resemble apoptosis. Here we investigate whether selective axon degeneration depends on some of the molecular machinery that mediates apoptosis, namely, the caspase family of cysteine proteases. We focus on two models of selective axon degeneration: Wallerian degeneration of transected axons and localized axon degeneration induced by local deprivation of neurotrophin. We show that caspase-3 is not activated in the axon during either form of degeneration, although it is activated in the dying cell body of the same neurons. Moreover, caspase inhibitors do not inhibit or retard either form of axon degeneration, although they inhibit apoptosis of the same neurons. Finally, we cannot detect cleaved substrates of caspase-3 and its close relatives immunocytochemically or caspase activity biochemically in axons undergoing Wallerian degeneration. Our results suggest that a neuron contains at least two molecularly distinct self-destruction programs, one for caspase-dependent apoptosis and another for selective axon degeneration.
Key words: neuron; apoptosis; nerve growth factor; optic nerve; sciatic nerve; retina; dorsal root ganglia
Copyright © 2000 Society for Neuroscience 0270-6474/00/2041333-09$05.00/0
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