Ricerc@Sapienza

Among the putative mechanisms involved in Down syndrome (DS) neurodegeneration, the reduction of cerebral glucose metabolism could be highly relevant by impacting the hexosamine biosynthetic pathway (HBP).
As reported in Alzheimer disease (AD), defective HBP leads to flawed protein O-GlcNAcylation coupled by a mutual increase of protein phosphorylation on Ser/Thr residues. This mutual relationship, gives to reduced O-GlcNAc the burden to affect several pathways crucial in the neurodegenerative process.Defects in glycosylation of APP and Tau have been extensively discuss in AD.
Our work aimed to unravel, for the first time, the role of reduced glucose metabolism and of aberrant protein O-GlcNAcylation in DS neuropathology.
We will investigate global O-GlcNAc/Ser/Thr phosphorylation ratio on the hippocampus of Ts2Cje (Ts2), mouse model of DS, at different ages. In parallel, we will analyse the relationship between altered O-GlcNAc levels, the activity of OGT and OGA enzymes (involved in O-GlcNAcylation cycling) and the O GlcNAcylation/phosphorylation ratio of APP and tau AD-related toxic products. At the end a glyco- proteomics approach, we will help to identify aberrantly O-glycosylated proteins to investigate novel molecular mechanism which may contribute to neurodegeneration in DS neuropathology.