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Proteomic identification of altered protein O-GlcNAcylation in a triple transgenic mouse model of Alzheimer's disease

dc.contributor.authorTramutola A.
dc.contributor.authorSharma N.
dc.contributor.authorBarone E.
dc.contributor.authorLanzillotta C.
dc.contributor.authorCastellani A.
dc.contributor.authorIavarone F.
dc.contributor.authorVincenzoni F.
dc.contributor.authorCastagnola M.
dc.contributor.authorButterfield D.A.
dc.contributor.authorGaetani S.
dc.contributor.authorCassano T.
dc.contributor.authorPerluigi M.
dc.contributor.authorDi Domenico F.
dc.date.accessioned2020-09-02T22:29:23Z
dc.date.available2020-09-02T22:29:23Z
dc.date.issued2018
dc.identifier10.1016/j.bbadis.2018.07.017
dc.identifier.citation1864, 10, 3309-3321
dc.identifier.issn09254439
dc.identifier.urihttps://hdl.handle.net/20.500.12728/6438
dc.descriptionPET scan analysis demonstrated the early reduction of cerebral glucose metabolism in Alzheimer disease (AD) patients that can make neurons vulnerable to damage via the alteration of the hexosamine biosynthetic pathway (HBP). Defective HBP leads to flawed protein O-GlcNAcylation coupled, by a mutual inverse relationship, with increased protein phosphorylation on Ser/Thr residues. Altered O-GlcNAcylation of Tau and APP have been reported in AD and is closely related with pathology onset and progression. In addition, type 2 diabetes patients show an altered O-GlcNAcylation/phosphorylation that might represent a link between metabolic defects and AD progression. Our study aimed to decipher the specific protein targets of altered O-GlcNAcylation in brain of 12-month-old 3×Tg-AD mice compared with age-matched non-Tg mice. Hence, we analysed the global O-GlcNAc levels, the levels and activity of OGT and OGA, the enzymes controlling its cycling and protein specific O-GlcNAc levels using a bi-dimensional electrophoresis (2DE) approach. Our data demonstrate the alteration of OGT and OGA activation coupled with the decrease of total O-GlcNAcylation levels. Data from proteomics analysis led to the identification of several proteins with reduced O-GlcNAcylation levels, which belong to key pathways involved in the progression of AD such as neuronal structure, protein degradation and glucose metabolism. In parallel, we analysed the O-GlcNAcylation/phosphorylation ratio of IRS1 and AKT, whose alterations may contribute to insulin resistance and reduced glucose uptake. Our findings may contribute to better understand the role of altered protein O-GlcNAcylation profile in AD, by possibly identifying novel mechanisms of disease progression related to glucose hypometabolism. © 2018
dc.language.isoen
dc.publisherElsevier B.V.
dc.subjectAlzheimer disease
dc.subjectGlucose metabolism
dc.subjectInsulin signaling
dc.subjectO-GlcNAcylation
dc.subjectPhosphorylation
dc.subjectglucose
dc.subjectglucose transporter 3
dc.subjectinsulin
dc.subjectproteome
dc.subjectserine
dc.subjecttau protein
dc.subjectthreonine
dc.subjectbeta n acetylhexosaminidase
dc.subjecthexosaminidase C
dc.subjectinsulin receptor substrate
dc.subjectIRS1 protein, human
dc.subjectn acetylglucosamine
dc.subjectn acetylglucosaminyltransferase
dc.subjectOGT protein, human
dc.subjectprotein
dc.subjectprotein kinase B
dc.subjectacylation
dc.subjectAlzheimer disease
dc.subjectanimal experiment
dc.subjectanimal model
dc.subjectanimal tissue
dc.subjectArticle
dc.subjectcerebellum
dc.subjectcontrolled study
dc.subjectenzyme activity
dc.subjectglucose metabolism
dc.subjectglucose transport
dc.subjecthippocampus
dc.subjecthomogenate
dc.subjectimmunofluorescence
dc.subjectinsulin resistance
dc.subjectinsulin signaling
dc.subjectmale
dc.subjectmass spectrometry
dc.subjectmolecular pathology
dc.subjectmouse
dc.subjectmouse model
dc.subjectneuropathology
dc.subjectnon insulin dependent diabetes mellitus
dc.subjectnonhuman
dc.subjectpriority journal
dc.subjectprotein degradation
dc.subjectprotein phosphorylation
dc.subjectprotein targeting
dc.subjectproteomics
dc.subjecttransgenic mouse
dc.subjecttwo dimensional electrophoresis
dc.subjectWestern blotting
dc.subjectAlzheimer disease
dc.subjectanimal
dc.subjectbrain
dc.subjectdisease model
dc.subjectfemale
dc.subjectgenetics
dc.subjecthuman
dc.subjectmetabolism
dc.subjectphosphorylation
dc.subjectprocedures
dc.subjectproteomics
dc.subjectAcetylglucosamine
dc.subjectAlzheimer Disease
dc.subjectAnimals
dc.subjectbeta-N-Acetylhexosaminidases
dc.subjectBrain
dc.subjectDisease Models, Animal
dc.subjectFemale
dc.subjectHumans
dc.subjectInsulin Receptor Substrate Proteins
dc.subjectMale
dc.subjectMice
dc.subjectMice, Transgenic
dc.subjectN-Acetylglucosaminyltransferases
dc.subjectPhosphorylation
dc.subjectProteins
dc.subjectProteomics
dc.subjectProto-Oncogene Proteins c-akt
dc.titleProteomic identification of altered protein O-GlcNAcylation in a triple transgenic mouse model of Alzheimer's disease
dc.typeArticle


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