The Dysregulation of OGT/OGA Cycle Mediates Tau and APP Neuropathology in Down Syndrome.
Amyloid beta-Protein Precursor
/ metabolism
Animals
Blotting, Western
Brain
/ metabolism
Disease Models, Animal
Down Syndrome
/ metabolism
Female
Fluorescent Antibody Technique
Immunoprecipitation
Male
Mice
N-Acetylglucosaminyltransferases
/ drug effects
Pyrans
/ pharmacology
Real-Time Polymerase Chain Reaction
Thiazoles
/ pharmacology
beta-N-Acetylhexosaminidases
/ drug effects
tau Proteins
/ metabolism
APP
Down syndrome
O-GlcNAcylation
OGT/OGA
autophagy
tau
Journal
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
ISSN: 1878-7479
Titre abrégé: Neurotherapeutics
Pays: United States
ID NLM: 101290381
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
accepted:
18
11
2020
pubmed:
2
12
2020
medline:
15
12
2021
entrez:
1
12
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33258073
doi: 10.1007/s13311-020-00978-4
pii: 10.1007/s13311-020-00978-4
pmc: PMC8116370
doi:
Substances chimiques
Amyloid beta-Protein Precursor
0
Pyrans
0
Thiazoles
0
tau Proteins
0
thiamet G
0
N-Acetylglucosaminyltransferases
EC 2.4.1.-
O-GlcNAc transferase
EC 2.4.1.-
hexosaminidase C
EC 3.2.1.50
beta-N-Acetylhexosaminidases
EC 3.2.1.52
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
340-363Subventions
Organisme : Sapienza Università di Roma
ID : RG1181642744DF59
Organisme : Sapienza Università di Roma
ID : RM11715C773949E3
Organisme : Sapienza Università di Roma
ID : RG116154C9214D1A
Organisme : Istituto Pasteur-Fondazione Cenci Bolognetti
ID : Under 45 U-4.IT
Organisme : Ministero della Salute
ID : GR-2018-12366381
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