title: Evidence that Wallerian degeneration and localized axon degeneration induced by local neurotrophin deprivation do not involve caspases.
abstract: 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.
authors.affiliation: Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, United Kingdom. jfinn@stanford.edu
authors.forename: J T
authors.initials: JT
authors.lastname: Finn
authors.forename: M
authors.initials: M
authors.lastname: Weil
authors.forename: F
authors.initials: F
authors.lastname: Archer
authors.forename: R
authors.initials: R
authors.lastname: Siman
authors.forename: A
authors.initials: A
authors.lastname: Srinivasan
authors.forename: M C
authors.initials: MC
authors.lastname: Raff
mesh_terms: D000818:Animals; D017209:Apoptosis; D001369:Axons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D005727:Ganglia, Spinal / Q000502:physiology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000503:physiopathology*; D009414:Nerve Growth Factors / Q000494:pharmacology / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D009900:Optic Nerve / Q000473:pathology / Q000502:physiology* / Q000503:physiopathology; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects / Q000502:physiology*; D012584:Sciatic Nerve / Q000473:pathology / Q000502:physiology* / Q000503:physiopathology; D014855:Wallerian Degeneration / Q000503:physiopathology*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D009414:Nerve Growth Factors; D003513:Cycloheximide; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases