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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

Lookup NU author(s): Professor Fiona MatthewsORCiD


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The accumulation of reactive oxygen species leading to oxidative damage and cell death plays an important role in a number of neurodegenerative disorders. FOXO(3)a, 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 FOXO(3)a 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 FOXO(3)a 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. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.

Publication metadata

Author(s): Fluteau A, Ince PG, Minett T, Matthews FE, Brayne C, Garwood CJ, Ratcliffe LE, Morgan S, Heath PR, Shaw PJ, Wharton SB, Simpson JE, MRC Cognitive Function Ageing

Publication type: Article

Publication status: Published

Journal: Neuroscience Letters

Year: 2015

Volume: 609

Pages: 11-17

Print publication date: 16/11/2015

Online publication date: 08/10/2015

Acceptance date: 01/10/2015

ISSN (print): 0304-3940

ISSN (electronic): 1872-7972

Publisher: Elsevier Ireland Ltd


DOI: 10.1016/j.neulet.2015.10.001


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Funder referenceFunder name
Oxford Biomedical Research Centre
Walton Centre NHS Foundation Trust, Liverpool
NIHR Cambridge Biomedical Research Centre
UKNIHR Biomedical Research Centre for Ageing
MRC/G9901400Department of Health and the Medical Research Council
MRJ004308/1Medical Research Council