The Dysregulation of OGT/OGA Cycle Mediates Tau and APP Neuropathology in Down Syndrome
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ORIGINAL ARTICLE
The Dysregulation of OGT/OGA Cycle Mediates Tau and APP Neuropathology in Down Syndrome Ilaria Zuliani 1 & Chiara Lanzillotta 1 & Antonella Tramutola 1 & Antonio Francioso 1 & Sara Pagnotta 1 & Eugenio Barone 1 & Marzia Perluigi 1 & Fabio Di Domenico 1 Accepted: 18 November 2020 # The Author(s) 2020
Abstract 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 OGlcNAcylation 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. Key Words O-GlcNAcylation . Down syndrome . OGT/OGA . APP . tau . autophagy
Introduction Down syndrome (DS; Trisomy 21) is the most common chromosomal disorder and the most frequent genetic cause of intellectual disability affecting about 6 million people worldwide [1, 2]. Because of the advances in health care and management of co-occurring illnesses, the life expectancy of people with DS has largely improved [3, 4]. The triplication of genes on chromosome 21 and of their products can alter diverse pathways, including those involved with brain development, metabolism, and neuronal networks [5, 6]. Individuals with DS are also more likely to develop certain pathological
* Fabio Di Domenico [email protected] 1
Department of Biochemical Sciences “A. Rossi Fanelli”, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
conditions, including hypothyroidism, autoimmune diseases, epilepsy, hematological disorders, and Alzheimer-like dementia [7]. The clinical manifestation of Alzhe
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