The slow Wallerian Degeneration (WldS) gene specifically protects axonal and synaptic compartments of neurons from a wide variety of degeneration-inducing stimuli, including; traumatic injury, Parkinson's disease, demyelinating neuropathies, some forms of motor neuron disease and global cerebral ischemia. The WldS gene encodes a novel Ube4b-Nmnat1 chimeric protein (WldS protein) that is responsible for conferring the neuroprotective phenotype. How the chimeric WldS protein confers neuroprotection remains controversial, but several studies have shown that expression in neurons in vivo and in vitro modifies key cellular pathways, including; NAD biosynthesis, ubiquitination, the mitochondrial proteome, cell cycle status and cell stress. Whether similar changes are induced in non-neuronal tissue and organs at a basal level in vivo remains to be determined. This may be of particular importance for the development and application of neuroprotective therapeutic strategies based around WldS-mediated pathways designed for use in human patients.
We have undertaken a detailed analysis of non-neuronal WldS expression in WldS mice, alongside gravimetric and histological analyses, to examine the influence of WldS expression in non-neuronal tissues. We show that expression of WldS RNA and protein are not restricted to neuronal tissue, but that the relative RNA and protein expression levels rarely correlate in these non-neuronal tissues. We show that WldS mice have normal body weight and growth characteristics as well as gravimetrically and histologically normal organs, regardless of WldS protein levels. Finally, we demonstrate that previously reported WldS-induced changes in cell cycle and cell stress status are neuronal-specific, not recapitulated in non-neuronal tissues at a basal level.
We conclude that expression of WldS protein has no adverse effects on non-neuronal tissue at a basal level in vivo, supporting the possibility of its safe use in future therapeutic strategies targeting axonal and/or synaptic compartments in patients with neurodegenerative disease. Future experiments determining whether WldS protein can modify responses to injury in non-neuronal tissue are now required.