Expression of the neuroprotective slow Wallerian degeneration (WldS) gene in non-neuronal tissues

<p>Abstract</p> <p>Background</p> <p>The slow Wallerian Degeneration (<it>Wld</it>^<it>S</it>) 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 <it>Wld</it>^{<it>S </it>}gene encodes a novel Ube4b-Nmnat1 chimeric protein (Wld^Sprotein) that is responsible for conferring the neuroprotective phenotype. How the chimeric Wld^Sprotein confers neuroprotection remains controversial, but several studies have shown that expression in neurons <it>in vivo </it>and <it>in vitro </it>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 <it>in vivo </it>remains to be determined. This may be of particular importance for the development and application of neuroprotective therapeutic strategies based around <it>Wld</it>^<it>S</it>-mediated pathways designed for use in human patients.</p> <p>Results</p> <p>We have undertaken a detailed analysis of non-neuronal <it>Wld</it>^{<it>S </it>}expression in <it>Wld</it>^{<it>S </it>}mice, alongside gravimetric and histological analyses, to examine the influence of <it>Wld</it>^{<it>S </it>}expression in non-neuronal tissues. We show that expression of <it>Wld</it>^{<it>S </it>}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 <it>Wld</it>^{<it>S </it>}mice have normal body weight and growth characteristics as well as gravimetrically and histologically normal organs, regardless of Wld^Sprotein levels. Finally, we demonstrate that previously reported <it>Wld</it>^<it>S</it>-induced changes in cell cycle and cell stress status are neuronal-specific, not recapitulated in non-neuronal tissues at a basal level.</p> <p>Conclusions</p> <p>We conclude that expression of Wld^Sprotein has no adverse effects on non-neuronal tissue at a basal level <it>in vivo</it>, 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 Wld^Sprotein can modify responses to injury in non-neuronal tissue are now required.</p