Expression of the neuroprotective slow Wallerian degeneration ( Wld ^S ) gene in non-neuronal tissues

Abstract

Background

The slow Wallerian Degeneration ( Wld ^S ) 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 Wld ^S gene encodes a novel Ube4b-Nmnat1 chimeric protein (Wld ^S protein) that is responsible for conferring the neuroprotective phenotype. How the chimeric Wld ^S 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 Wld ^S -mediated pathways designed for use in human patients.

Results

We have undertaken a detailed analysis of non-neuronal Wld ^S expression in Wld ^S mice, alongside gravimetric and histological analyses, to examine the influence of Wld ^S expression in non-neuronal tissues. We show that expression of Wld ^S 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 Wld ^S mice have normal body weight and growth characteristics as well as gravimetrically and histologically normal organs, regardless of Wld ^S protein levels. Finally, we demonstrate that previously reported Wld ^S -induced changes in cell cycle and cell stress status are neuronal-specific, not recapitulated in non-neuronal tissues at a basal level.

Conclusions

We conclude that expression of Wld ^S 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 Wld ^S protein can modify responses to injury in non-neuronal tissue are now required.