Adeline Fluteau
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
Paul G. Ince
Thais Minett
Professor Fiona Matthews F.Matthews@hull.ac.uk
Pro-Vice-Chancellor Research and Enterprise
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 |