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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

Fluteau, Adeline; Ince, Paul G.; Minett, Thais; Matthews, Fiona E.; Brayne, Carol; Garwood, Claire J.; Ratcliffe, Laura E.; Morgan, Sarah; Heath, Paul R.; Shaw, Pamela J.; Wharton, Stephen B.; Simpson, Julie E.

Authors

Adeline Fluteau

Paul G. Ince

Thais Minett

Carol Brayne

Claire J. Garwood

Laura E. Ratcliffe

Sarah Morgan

Paul R. Heath

Pamela J. Shaw

Stephen B. Wharton

Julie E. Simpson



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.

Citation

Fluteau, A., Ince, P. G., Minett, T., Matthews, F. E., Brayne, C., Garwood, C. J., Ratcliffe, L. E., Morgan, S., Heath, P. R., Shaw, P. J., Wharton, S. B., & Simpson, J. E. (2015). 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. Neuroscience letters, 609, 11-17. https://doi.org/10.1016/j.neulet.2015.10.001

Journal Article Type Article
Publication Date Nov 16, 2015
Deposit Date Dec 8, 2023
Journal Neuroscience Letters
Print ISSN 0304-3940
Electronic ISSN 1872-7972
Publisher Elsevier
Volume 609
Pages 11-17
DOI https://doi.org/10.1016/j.neulet.2015.10.001
Public URL https://hull-repository.worktribe.com/output/4453834