Hardingham, Giles

Skehel, Paul

Mubarak, Bashayer Rashed A

Al-Mubarak, Bashayer

2013-10-28T11:49:22Z

2013-10-28T11:49:22Z

2013-06-29

Oxidative stress is a feature of many chronic neurodegenerative diseases as well as a contributing factor in acute disorders including stroke. Fork head class of transcription factors (Foxos) play a key role in promoting oxidative stress-induced apoptosis in neurons through the upregulation of a number of pro-apoptotic genes. Here I demonstrate that synaptic NMDA receptor activity not only promotes Foxos nuclear exclusion but also suppresses the expression of Foxo1 in a PI3K-dependent fashion. I also found that Foxo1 is in fact, a Foxo target gene and that it is subject to a feed-forward inhibition by synaptic activity, which is thought to result in longerterm suppression of Foxo downstream gene expression than previously thought. The nuclear factor (erythroid 2-related) factor 2 (Nrf2) is another transcription factor involved in oxidative stress and the key regulator of many genes, whose products form important intrinsic antioxidant systems. In the CNS, artificial activation of Nrf2 in astrocytes has been shown to protect nearby neurons from oxidative insults. However, the extent to which Nrf2 in astrocytes could respond to endogenous signals such as mild oxidative stress is less clear. The data presented herein, demonstrate for the first time that endogenous Nrf2 could be activated by mild oxidative stress and that this activation is restricted to astrocytes. Contrary to the established dogma, I found that mild oxidative stress induces the astrocytic Nrf2 pathway in a manner distinct from the classical Keap1 antagonism employed by prototypical Nrf2 inducers. The mechanism was found to involve direct regulation of Nrf2's transactivation properties. Overall these results advance our knowledge of the molecular mechanism(s) associated with the control of endogenous antioxidant defences by physiological signals.

http://hdl.handle.net/1842/8057

en

The University of Edinburgh

AL-MUBARAK, B., SORIANO, F. X. & HARDINGHAM, G. E. 2009. Synaptic NMDAR activity suppresses FOXO1 expression via a cis-acting FOXO binding site: FOXO1 is a FOXO target gene. Channels (Austin), 3, 233-8.

BELL, K. F., AL-MUBARAK, B., FOWLER, J. H., BAXTER, P. S., GUPTA, K., TSUJITA, T., CHOWDHRY, S., PATANI, R., CHANDRAN, S., HORSBURGH, K., HAYES, J. D. & HARDINGHAM, G. E. 2011a. Mild oxidative stress activates Nrf2 in astrocytes, which contributes to neuroprotective ischemic preconditioning. Proc Natl Acad Sci U S A, 108, E1-2; author reply E3-4.

BELL, K. F., FOWLER, J. H., AL-MUBARAK, B., HORSBURGH, K. & HARDINGHAM, G. E. 2011b. Activation of Nrf2-regulated glutathione pathway genes by ischemic preconditioning. Oxid Med Cell Longev, 2011, 689524.

MARTEL, M. A., RYAN, T. J., BELL, K. F., FOWLER, J. H., MCMAHON, A., AL-MUBARAK, B., KOMIYAMA, N. H., HORSBURGH, K., KIND, P. C., GRANT, S. G., WYLLIE, D. J. & HARDINGHAM, G. E. 2012. The subtype of GluN2 C-terminal domain determines the response to excitotoxic insults. Neuron, 74, 543-56.

neurons

astrocytes

oxidative stress

Nrf2

Foxos

Keap1

antioxidant defences

Control of anti-apoptotic and antioxidant pathways in neural cells

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy