title: The nuclear retention of transcription factor FOXO3a correlates with a DNA damage response and increased glutamine synthetase expression by astrocytes suggesting a neuroprotective role in the ageing brain.
abstract: The accumulation of reactive oxygen species leading to oxidative damage and cell death plays an important role in a number of neurodegenerative disorders. FOXO3a, the main isoform of FOXO transcription factors, mediates the cellular response to oxidative stress by regulating the expression of genes involved in DNA repair and glutamine metabolism, including glutamine synthetase (GS). Immunohistochemical investigation of the population-based neuropathology cohort of the Medical Research Council's Cognitive Function and Ageing Study (MRC CFAS) demonstrates that nuclear retention of FOXO3a significantly correlates with a DNA damage response and with GS expression by astrocytes. Furthermore, we show that GS expression correlates with increasing Alzheimer-type pathology in this ageing cohort. Our findings suggest that in response to oxidative stress, the nuclear retention of FOXO3a in astrocytes upregulates expression of GS as a neuroprotective mechanism. However, the activity of GS may be compromised by increasing levels of oxidative stress in the ageing brain resulting in dysfunctional enzyme activity, neuronal excitotoxic damage and cognitive impairment.
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, United Kingdom; MRC Human Genetics Unit, University of Edinburgh, United Kingdom.
authors.forename: Adeline
authors.initials: A
authors.lastname: Fluteau
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, United Kingdom.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ince
authors.affiliation: Institute of Public Health, University of Cambridge, United Kingdom; Department of Radiology, University of Cambridge, United Kingdom.
authors.forename: Thais
authors.initials: T
authors.lastname: Minett
authors.affiliation: MRC Biostatistics Unit, Cambridge, United Kingdom; Institute of Health and Society, University of Newcastle, United Kingdom; Faculty of Life Sciences, University of Manchester, United Kingdom.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Matthews
authors.affiliation: Institute of Public Health, University of Cambridge, United Kingdom.
authors.forename: Carol
authors.initials: C
authors.lastname: Brayne
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, United Kingdom.
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Garwood
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, United Kingdom.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Ratcliffe
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Morgan
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, United Kingdom.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Heath
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, United Kingdom.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, United Kingdom. Electronic address: s.wharton@sheffield.ac.uk.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Wharton
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, United Kingdom.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Simpson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D004249:DNA Damage; D003704:Dementia / Q000378:metabolism* / Q000473:pathology; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism*; D006801:Humans; D008297:Male; D013702:Temporal Lobe / Q000378:metabolism / Q000473:pathology
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D005974:Glutamate-Ammonia Ligase
keywords: Ageing brain; Alzheimer’s; Astrocyte; DNA damage response; FOXO3a; Glutamine synthetase; Pathology; neurone