Axon Death Prevented: Wld s and Other Neuroprotective Molecules: A Dissertation

Abstract

A common feature of many neuropathies is axon degeneration. While the reasons for degeneration differ greatly, the process of degeneration itself is similar in most cases. Axon degeneration after axotomy is termed ‘Wallerian degeneration,’ whereby injured axons rapidly fragment and disappear after a short period of latency (Waller, 1850). Wallerian degeneration was thought to be a passive process until the discovery of the Wallerian degeneration slow (Wld) mouse mutant. In these mice, axons survive and function for weeks after nerve transection. Furthermore, when the full-length protein is inserted into mouse models of disease with an axon degeneration phenotype (such as progressive motor neuronopathy), Wld is able to delay disease onset (for a review, see Coleman, 2005). Wld has been cloned and was found to be a fusion event of two neighboring genes: Ube4b, which encodes an ubiquitinating enzyme, and NMNAT-1 (nicotinamide mononucleotide adenylyltransferase-1), which encodes a key factor in NAD (nicotinamide adenine dinucleotide) biosynthesis, joined by a 54 nucleotide linker span (Mack et al., 2001). To address the role of Wld domains in axon protection and to characterize the subcellular localization of Wld in neurons, our lab developed a novel method to study Wallerian degeneration in Drosophila in vivo (MacDonald et al., 2006). Using this method, we have discovered that mouse Wld can also protect Drosophila axons for weeks after acute injury, indicating that the molecular mechanisms of Wallerian degeneration are well conserved between