Evidence that wallerian degeneration and localized axon degeneration induced by local neurotrophin deprivation do not involve caspases

The selective degeneration of an axon, without the death of the parent neur on, can occur in response to injury, in a variety of metabolic, toxic, and inflammatory disorders, and during normal development. Recent evidence sugg ests that some forms of axon degeneration involve an active and regulated p rogram of self-destruction rather than a passive "wasting away" and in this respect and others resemble apoptosis. Here we investigate whether selecti ve axon degeneration depends on some of the molecular machinery that mediat es apoptosis, namely, the caspase family of cysteine proteases. We focus on two models of selective axon degeneration: Wallerian degeneration of trans ected axons and localized axon degeneration induced by local deprivation of neurotrophin. We show that caspase-3 is not activated in the axon during e ither 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 s ame 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 neur on contains at least two molecularly distinct self-destruction programs, on e for caspase-dependent apoptosis and another for selective axon degenerati on.