Control of neuroprotection through NMDA receptor-dependent regulation of antioxidant status.

Lead Research Organisation: University of Edinburgh
Department Name: Biomedical Sciences

Abstract

Nerve cells (neurons) communicate by releasing chemical messengers onto each other, which are detected by specialised receptors. Low-level activation of an important receptor, the NMDA receptor (NMDAR), causes activation of signals that improve a neuron‘s chance of survival. We aim to understand the exact nature of these signals. Understanding the brain‘s natural neuroprotective mechanisms is important, since malfunction of these mechanisms may contribute to neurodegeneration in certain debilitating disorders (e.g.Alzheimer‘s, ALS, Parkinson‘s), and also neurodevelopmental disorders associated with too little NMDAR activity (e.g.Foetal Alcohol Syndrome). In contrast to the beneficial effects of modest NMDAR activity, too much NMDAR activation can kill neurons. This can occur when the brain is starved of blood supply, as happens in a stroke, and can even happen in certain neurodegenerative diseases. However, these disorders cannot be treated by blocking the NMDAR with drugs, since this is harmful too. We will investigate how blocking downstream consequences of NMDAR overactivation, rather than the NMDAR itself, can protect neurons in models of disease and injury, possibly leading to therapeutic targets for stroke or novel treatments. Our investigations will include studies on stem cell-derived human neurons, a theoretically limitless source of neurons with potentially increased relevance to human disease.

Technical Summary

Neuronal death is implicit in all neurodegenerative conditions. Activation of the NMDA subtype of glutamate receptor (NMDAR) regulates calcium-dependent survival and death pathways through a ‘bell-shaped‘ dose-response curve: modest activity is neuroprotective, but too much and too little NMDAR activity is harmful. Published and preliminary work show that oxidative stress contributes to neuronal death induced by both NMDAR hyper- and hypo-activity and that conversely, modest synaptic NMDAR activity boosts antioxidant defenses.
We will investigate the regulation of intrinsic neuronal antioxidant defenses by protective NMDAR signaling and determine how boosting defenses can prevent death due to NMDAR hypo- and hyper-activity. Studies will involve mechanistic investigation using primary neurons, and testing hypotheses in mouse models of NMDAR hypo- and hyperactivity-induced damage. To translate our neuroprotection studies into human neurons we will exploit recent advances to study neurons derived from human embryonic stem cells.

Aims:
1.Determine novel activity-dependent mechanisms that boost intrinsic antioxidant defenses in neurons.
We will investigate events that trigger enhancement of the glutathione antioxidant system, and also disinhibition of Nrf2, a transcription factor which induces antioxidant genes. Characterisation of endogenous pathways that control antioxidant defenses may help understand neurological disorders associated with oxidative damage, and reveal new therapeutic targets. Further, by elucidating the antioxidant effects of synaptic NMDAR activity we can predict the potentially harmful consequences of NMDAR blockade.
2.Define antioxidant strategies for protecting neurons from damage due to too much or too little NMDAR activity.
Using genetic approaches and recently-developed pharmacological activators of neuronal Nrf2, we will investigate how boosting antioxidant defenses reduces neurodegeneration due to NMDAR hypo- or hyper-activity. In treating disorders associated with excitotoxicity, this approach may be better-tolerated than NMDAR blockade, and be effective in injury models where NMDAR pro-death and pro-survival signals operate at different times post-trauma.
3.Determine the differences between activity-regulated genes in mouse vs. human neurons, and the extent to which antioxidant pathways can be manipulated to block excitotoxic/oxidative death.
Defining neuroprotective/destructive pathways in rodent systems will generate hypotheses applicable to human neurons. However, species-specific differences may exist and cloud their direct translation. We will define the similarities and interspecies differences in activity-regulated gene expression and neuroprotection between human and mouse neurons, providing a bridge for translating mouse results into man. We will also investigate the capacity for human neuronal antioxidant defenses to be manipulated, potentially assisting development of neuroprotective drugs, or neuroprotective strategies in future stem cell-based therapies.

Publications

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Bell K (2011) The influence of synaptic activity on neuronal health in Current Opinion in Neurobiology

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Bell KF (2011) Activation of Nrf2-regulated glutathione pathway genes by ischemic preconditioning. in Oxidative medicine and cellular longevity

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Bell KF (2011) CNS peroxiredoxins and their regulation in health and disease. in Antioxidants & redox signaling

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Bell KF (2011) Mild oxidative stress activates Nrf2 in astrocytes, which contributes to neuroprotective ischemic preconditioning. in Proceedings of the National Academy of Sciences of the United States of America

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Bilican B (2012) Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. in Proceedings of the National Academy of Sciences of the United States of America

 
Description Marie Curie Initial Training Network FP7
Amount £233,000 (GBP)
Organisation Marie Sklodowska-Curie Actions 
Sector Charity/Non Profit
Country Global
Start 09/2012 
End 09/2015
 
Description UK Dementia Research Institute (UK DRI) at the University of Edinburgh
Amount £198,000 (GBP)
Funding ID Capital portion of the award is MC_PC_17113 
Organisation UK Dementia Research Institute 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2017 
End 09/2022
 
Description Mitochondrial calcium 
Organisation Heidelberg University
Department Neurobiology Institute
Country Germany 
Sector Academic/University 
PI Contribution Investigation of the effect of over-expressing and knocking down Mcu on mitochondrial calcium uptake on excitotoxicity in neurons
Collaborator Contribution Supplying vectors encoding shRNAs to knock down Mcu gene
Impact Publications pending
Start Year 2012
 
Description NMDA receptor function and physiology 
Organisation Charité - University of Medicine Berlin
Country Germany 
Sector Academic/University 
PI Contribution Directing and leading the projects centred on neuroprotective and destructive signaling by NMDARs
Collaborator Contribution Collaborative contribution to 18344994, studying in vivo effects of NMDAR blockadeCollaborative contributions to papers that I led-PMID 18344994, 18378405, 19221512, 20164347, plus those led by others 22022974
Impact Published papers as indicated above.
Start Year 2007
 
Description NMDA receptor function and physiology 
Organisation University of Edinburgh
Department Centre for Integrative Physiology
Country United Kingdom 
Sector Academic/University 
PI Contribution Directing and leading the projects centred on neuroprotective and destructive signaling by NMDARs
Collaborator Contribution Collaborative contribution to 18344994, studying in vivo effects of NMDAR blockadeCollaborative contributions to papers that I led-PMID 18344994, 18378405, 19221512, 20164347, plus those led by others 22022974
Impact Published papers as indicated above.
Start Year 2007
 
Description Study of Nrf2-mediated neuroprotection 
Organisation University of Dundee
Department Biomedical Research Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution I led all the studies focussed on neuroprotection models and mechanisms.
Collaborator Contribution Collaborative inputs to published papers PMID 22095276, 21177433, 18761713 through the supply of genetically modified miceCollaborative inputs to published papers PMID 22095276, 21364553, 21364553, 20431962 through the generation of human ES cell-derived neurons and astrocytes
Impact Published papers PMID is listed in the details of individual partners
Start Year 2008
 
Description Study of Nrf2-mediated neuroprotection 
Organisation University of Edinburgh
Department Centre for Clinical Brain Sciences (CCBS)
Country United Kingdom 
Sector Academic/University 
PI Contribution I led all the studies focussed on neuroprotection models and mechanisms.
Collaborator Contribution Collaborative inputs to published papers PMID 22095276, 21177433, 18761713 through the supply of genetically modified miceCollaborative inputs to published papers PMID 22095276, 21364553, 21364553, 20431962 through the generation of human ES cell-derived neurons and astrocytes
Impact Published papers PMID is listed in the details of individual partners
Start Year 2008