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The Dysregulation of OGT/OGA Cycle Mediates Tau and APP Neuropathology in Down Syndrome.

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics (2020-12-02)
Ilaria Zuliani, Chiara Lanzillotta, Antonella Tramutola, Antonio Francioso, Sara Pagnotta, Eugenio Barone, Marzia Perluigi, Fabio Di Domenico

Protein O-GlcNAcylation is a nutrient-related post-translational modification that, since its discovery some 30 years ago, has been associated with the development of neurodegenerative diseases. As reported in Alzheimer's disease (AD), flaws in the cerebral glucose uptake translate into reduced hexosamine biosynthetic pathway flux and subsequently lead to aberrant protein O-GlcNAcylation. Notably, the reduction of O-GlcNAcylated proteins involves also tau and APP, thus promoting their aberrant phosphorylation in AD brain and the onset of AD pathological markers. Down syndrome (DS) individuals are characterized by the early development of AD by the age of 60 and, although the two conditions present the same pathological hallmarks and share the alteration of many molecular mechanisms driving brain degeneration, no evidence has been sought on the implication of O-GlcNAcylation in DS pathology. Our study aimed to unravel for the first time the role of protein O-GlcNacylation in DS brain alterations positing the attention of potential trisomy-related mechanisms triggering the aberrant regulation of OGT/OGA cycle. We demonstrate the disruption of O-GlcNAcylation homeostasis, as an effect of altered OGT and OGA regulatory mechanism, and confirm the relevance of O-GlcNAcylation in the appearance of AD hallmarks in the brain of a murine model of DS. Furthermore, we provide evidence for the neuroprotective effects of brain-targeted OGA inhibition. Indeed, the rescue of OGA activity was able to restore protein O-GlcNAcylation, and reduce AD-related hallmarks and decreased protein nitration, possibly as effect of induced autophagy.

Product Number
Product Description

Fluoromount Aqueous Mounting Medium, for use with fluorescent dye-stained tissues
Anti-O-Linked N-Acetylglucosamine Antibody, clone RL2, clone RL2, from mouse
Monoclonal Anti-3-Nitrotyrosine antibody produced in mouse, clone 18G4, purified immunoglobulin, buffered aqueous glycerol solution
Anti-Mouse IgG (Fab specific)–Alkaline Phosphatase antibody produced in goat, affinity isolated antibody, buffered aqueous solution
Anti-Sheep IgG (whole molecule)–Peroxidase antibody produced in donkey, affinity isolated antibody, buffered aqueous solution
Anti-Goat IgG (whole molecule)–Alkaline Phosphatase antibody produced in rabbit, affinity isolated antibody, buffered aqueous glycerol solution
Anti-APP antibody produced in rabbit, 1 mg/mL, affinity isolated antibody