WldS mutant mice and their transgenic equivalents show 10-fold slower axonal and synaptic degeneration in response to either peripheral or central nerve lesions, due to overexpression of an Ube4b/Nmnat-1 chimeric protein (Gillingwater & Ribchester, 2001; Mack et al., 2001). The WldS protein forms dense nuclear aggregates, suggesting that the gene exerts its neuroprotective effects indirectly (Gillingwater et al., 2004; Araki et al, 2004). Here we examined the hypothesis that the WldS phenotype is due to transcriptional regulation of other genes. Western analysis and immunostaining of brains isolated from WldS mice killed by cervical dislocation (Home Office Schedule 1) established cerebellar granule cells as a rich source of WldS protein. We therefore extracted cerebellar mRNA from three WldS and three WT control mice and analysed gene expression using Affymetrix microarrays. Changes in the levels of candidate genes were validated by RT-PCR on the same mRNA extracts. As expected, there was a significant increase in Nmnat-1 expression in the WldS cerebellum, but several other genes were more than 5-fold up- or down-regulated, the largest change being a 10-fold downregulation in mRNA for pituitary tumour transforming gene (pttg-1). To test whether downregulation of pttg-1 was caused by WldS expression, we transfected cultures of human embryonic kidney (HEK) 293 cell lines with a fused WldS-EGFP construct, to allow for visual confirmation of protein expression. Semi-quantitative RT-PCR showed gene-dose dependent downregulation of the human PTTG-1 mRNA, 4 days after WldS transfection. Sciatic nerve section under ketamine/xylazine anaesthesia (respectively 100/10 mg/kg, IP) in nine pttg-1 (-/-) null mutant mice showed no evidence of protection of neuromuscular synapses by 48 hours. However, confocal microscopy revealed several intact axon fragments extending over 1mm in length in the distal tibial nerve. We conclude that expression of the WldS gene results in downregulation of the pttg-1 gene. However, the neuroprotective phenotype of WldS mice is not explained by downregulation of only this gene.