Wallerian degeneration as a window to peripheral neuropathy

Wallerian degeneration represents axonal degeneration in its purest form. When a nerve fiber is transected, a series of events is set in motion that results in dissolution of the distal axon, remodeling of the nerve fiber constituents (i.e., Schwann cells, basal lamina) and ultimately regeneration of the fiber by growth of new axons. Pathologically, the axon degeneration and regeneration that occur in human and experimental peripheral neuropathies is quite similar to Wallerian degeneration, and is appropriately described as ‘‘Wallerian-like’’. This similarity has allowed researchers to use experimental Wallerian degeneration as a tool for studying the pathogenesis and potential treatments of peripheral neuropathies. This discussion addresses our current understanding of axonal degeneration and relates the findings in experimental models to what is known about the pathogenesis of peripheral neuropathies. Topics of interest are: (1) the roles of calcium and calcium-activated proteases in cytoskeletal disruption and regeneration; (2) axonal transport of proteins in the day-to-day maintenance of the axon; and (3) the ‘‘triggering’’ events that lead to both Wallerian and Wallerian-like degeneration of nerve fibers. The WldS mouse, as introduced in the historical review of Wallerian degeneration (Koeppen, this symposium), is a remarkable discovery whose existence validates the concept that Wallerian degeneration is not the result of mere ‘‘starvation’’ of the axon for newly synthesized proteins. Wallerian degeneration is likely an active process involving the activation of a ‘‘death program’’ in axons. The conceptual link between Wallerian degeneration and peripheral neuropathy is supported by our demonstration that WldS mice are resistant to peripheral neuropathy, and also raises the possibility of using the WldS gene product for prevention of axonal degeneration in the treatment of peripheral neuropathies. We have used in vitro and in vivo models to study Wallerian degeneration and experimental peripheral neuropathy. In dorsal root explant cultures, we showed that both are dependent on millimolar levels of calcium, and that inhibition of the calcium-activated protease calpain protects against axonal degeneration due to trauma or toxic exposure [1]. This in vitro model led us to examine the strategy of systemic calpain inhibition in a whole animal model of Taxol neuropathy. Mice treated with high doses of this cancer chemotherapy agent develop a neuropathy quantifiable by behavioral, electrophysiologic, and pathologic measures. Continuous administration of the ketoamide calpain inhibitor AK295 improved all of these measures of neuropathy while showing no overt evidence of toxicity [2]. This remarkable finding suggests that the pharmacological strategy for protecting axons may be useful for human neuropathies. Moreover, in any case where axonal degeneration may be predicted (i.e., in chemotherapy, diabetes mellitus, human immunodeficiency virus infection, and Charcot-Marie-Tooth disease), we may be able to protect patients from the symptoms and disabilities associated with the neuropathic effects of these diseases. We have also tested the WldS mouse for its ability to resist neuropathy. This experimental strategy is based on further linking the process of Wallerian degeneration with peripheral neuropathy. We found that he WldS mouse is resistant to peripheral neuropathy using the same Taxolmediated axonal degeneration model described above [3]. We have gone on to show that the WldS gene, Ube4b/nmnat [4], when inserted into a viral vector can also deliver