Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene

Axons and their synapses distal to an injury undergo rapid Wallerian degene ration, but axons in the C57BL/Wld(S) mouse are protected. The degenerative and protective mechanisms are unknown. We identified the protective gene, which encodes an N-terminal fragment of ubiquitination factor E4B (Ube4b) f used to nicotinamide mononucleotide adenylyltransferase (Nmnat), and showed that it confers a dose-dependent block of Wallerian degeneration. Transect ed distal axons survived for two weeks, and neuromuscular junctions were al so protected. Surprisingly, the Wld protein was located predominantly in th e nucleus, indicating an indirect protective mechanism. Nmnat enzyme activi ty, but not NAD(+) content, was increased fourfold in Wld(S) tissues. Thus, axon protection is likely to be mediated by altered ubiquitination or pyri dine nucleotide metabolism.