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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.

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