The C57BL/Wld s mouse is a mutant strain of mouse that shows greatly slowed Wallerian degeneration both in the central and peripheral nervous system. Using immunohistochemistry, immunofluorescence and Western blotting, we have investigated the distribution of the chimeric Wld s protein and its different components in neurons of the CNS of Wld s mice and wild-type C57BL/6J mice. The expression of the Wld s protein is restricted to the nucleus in Wld s mice. Wld s was not detected in axons. The Wld s mice express both the normal and chimeric forms of ubiquitination factor E4 (Ube 4b) and nicotinamide mononucleotide adenylyltransferase-1 (Nmnat-1). The normal forms were expressed both in the cytoplasm and the nuclei of neurons in Wld s mice and wild-type mice, and were also present in the axon. The normal form of Ube4b, mono- and poly-ubiquitin and IkappaBalpha, a substrate of Ube4b, were not differentially expressed in Wld s mice compared with wild-type mice. However, the expression of both the normal and mutant forms of Nmnat-1 was higher in the nuclei of Wld s mice compared with wild-type mice. Therefore, axon protection in Wld s mice does not appear to be controlled by expression of Wld s protein in the axons per se and also is unlikely to be related to the different activity of Ube4b either in general ubiquitination or toward this particular substrate. The increased Nmnat-1 activity in the nucleus of Wld s mice compared with wild-type mice seems to be a significant factor in the axon protection. It is not known whether the expression of the Nmnat-1 in the axon is significant.