Gene Expression Profiling in Cells with Enhanced ?-Secretase Activity

Magold, Alexandra I.; Cacquevel, Matthias; Fraering, Patrick C.

We further report here that UPP1 transcript levels are increased with enhanced c-secretase activity (by 39.2-fold). UPP1 encodes for uridine phosphorylase (UPase), an enzyme that catalyzes the reversible phosphorylytic cleavage of uridine and deoxyuridine to uracil and ribose-or deoxyribose-1-phosphate [69] . UPP1 expression has been extensively connected to cancer, stem cells and inflammation such as multiple sclerosis [70] [71] [72] [73] [74] [75] [76] [77] . UPase is induced by vitamin D3 and a mixture of inflammatory cytokines, Interferon gamma, TNF-alpha and IL-1, with the latter two being upregulators of Ptprg [78] . Increased UPP1 transcript levels, associated with enhanced UPase activity cleaving uridine, would potentially have inhibitory effects on several pathways downstream of uridine, like RNA/DNA and membrane synthesis, as well as protein glycosylation, which would in turn trigger long-term neurodegeneration. Particularly, decreased membrane synthesis, in the case of synaptic membranes, would also reduce synaptic activity and plasticity. In support of that, TNF-a and IL-1, inducers of UPP1, alter lipid metabolism and stimulate production of eicosanoids, ceramide and reactive oxygen species that potentiate CNS injuries and certain neurological disorders [33] . Interestingly, this hypothesis offers an explanation for the multitude of beneficial effects of orally administered DHA and uridine on memory, neuronal health, regeneration and membrane synthesis in traumatic and chronic neuropathological conditions [33, 34] .