Impairment of yeast PRPP synthetase activity affects cell signalling - a model for management and treatment for human neuropathies?

SNPs associated with Charcot-Marie-Tooth disease (CMTX5) and Arts syndrome, clinical and heterogenous neurological disorders, have been mapped to the human PRPS1 gene which encodes PRPP synthetase (Prs). Prs links carbon and nitrogen metabolism to produce PRPP (phospho-D-ribosyl-α-1pyrophosphate) required for the de novo and salvage pathways of purines and pyrimidines, tryptophan and histidine. CMTX5, a common inherited human disorder occurs with a frequency of 1 in 2,500. Arts syndrome affects mainly males at a frequency of 1 in 106 leading to death in early childhood. Symptoms of Arts syndrome are delayed motor development, ataxia and increased susceptibility to upper respiratory tract infections whereas CMTX5 is characterised by peripheral neuropathy. There are five paralogous PRS genes in yeast. PRS1, PRS3 and PRS5 may have arisen from the prototype PRS-encoding genes, PRS2 and PRS4, by duplication followed by acquisition of insertions (NHRs). Genocopies which mimic the SNPs associated with CMTX5 and Arts syndrome were created to examine their impact on yeast physiology. Caffeine sensitivity and Rlm1 expression of the genocopies p.L115T (CMTX5) and p.Q133P (Arts syndrome) were increased at ambient temperature, indicating that these mutations may influence the folding of Prs1, thus impacting on the phosphorylation status of Slt2 and NHR1-1/Slt2 interaction, thereby linking primary metabolism with cell signalling. Deletion of PRS1, PRS3 or PRS5 causes sensitivity to lithium, a natural Gsk3 inhibitor, suggesting the involvement of Prs in neuropathology. NHR5-2 of Prs5 contains three neighbouring phosphosites which, when mutated, compromise Rlm1 and Fks2 expression and weakens the interaction of Prs5 with the kinase Rim11, one of the four yeast Gsk3 paralogues. Removal of NHR3-1 of Prs3 destabilises the Prs1/Prs3 heterodimer, leads to caffeine sensitivity, lowers Rlm1 expression and prevents rescue of a synthetically lethal prs3Δ prs5Δ strain. Since deletion of PRS5 causes rapamycin resistance we postulate an interaction between TOR signalling and PRPP synthetase, thus adding a new dimension to the application of yeast research in the discovery of novel therapeutic targets for the treatment of the human neuropathies, CMTX5 and Arts syndrome.