Nitric oxide mediated toxicity in neurodegeneration and disease

Lead Research Organisation: MRC Toxicology Unit

Abstract

In order for the brain to function it requires undisturbed communication between neurons which form a network of complex interactions. The signalling between neurons, via synapses, can be easily disturbed and a fine balance between repair and unhealthy or toxic mechanisms can modulate this communication. In many neurological diseases, this function has been reported to be compromised and nitric oxide (NO), a gaseous molecule has been implicated in those diseases.
The key aims of the proposal are to determine how NO disturbs the communication between neurons and the pathways by which this gas interferes with components of the neuronal communication network.
In order to identify the effects of NO signalling we will initially perform functional studies in which NO signalling is modulated by pharmacological and genetic methods. This will give an answer what the mechanisms are by which NO can interfere with neuronal function. Neurological diseases are one of the main causes for death in developed countries. It is imperative that new treatments for such conditions being developed and many ongoing research projects aim to understand the basic dysfunctional signalling pathway early in disease. One of those areas of research focuses on NO signalling but it has yet to be established how NO contributes to dysfunction. Therefore it will be important to develop strategies to interfere with abnormal NO signalling which will benefit patients affected by neurological conditions. An improved understanding of early key pathways leading to these conditions will allow the development of treatments to reverse or slow down pathology progression

Technical Summary

This programme aims to investigate cell signalling pathways involved in Nitric Oxide (NO)-induced neurotoxicity and identify putative targets for therapeutic intervention(s). Abnormal NO signalling has been implicated in several neurodegenerative diseases related to misfolded proteins or induced by exogenous factors such as pesticides (i.e. organophosphates, OPs) but its exact contribution to neuronal death remains elusive due to the great complexity of downstream nitrergic targets.
Elevated NO levels, as seen in many diseased states, can lead to the formation of cytotoxic peroxynitrite (ONOO-) which in turn can directly modulate a wide range of protein functions via nitration of tyrosine residues (3-Nitrotyrosination). Furthermore, at higher concentrations, toxic NO signalling can alter the functioning of proteins in a process known as S-nitrosylation. Both signalling pathways have been widely reported, rendering it of similar functional importance to phosphorylation and ubiquitination processes. The key aim of this proposal is the identification of substrates subjected to this regulation by nitrergic signalling pathways. To date, little is known as to what extent NO-mediated post-translational modifications contribute to or exacerbate neuronal dysfunction. The identification of novel nitrergic signalling pathways and correlation with early functional changes prior to any disease onset will allow a better understanding of cytotoxic NO signalling.

Publications

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Agostini M (2011) microRNA-34a regulates neurite outgrowth, spinal morphology, and function. in Proceedings of the National Academy of Sciences of the United States of America

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Augustin H (2017) Myostatin-like proteins regulate synaptic function and neuronal morphology. in Development (Cambridge, England)

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Bourgognon JM (2019) The metabolome identity: basis for discovery of biomarkers in neurodegeneration. in Neural regeneration research

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Bradley SA (2016) Nitric Oxide-Mediated Posttranslational Modifications: Impacts at the Synapse. in Oxidative medicine and cellular longevity

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Bradley SJ (2017) M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss. in The Journal of clinical investigation

 
Description AgeUK and RNID PhD Scholarship to study Presbycusis
Amount £35,000 (GBP)
Organisation Action on Hearing Loss 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2010 
End 12/2013
 
Description AgeUK and RNID PhD Scholarship to study Presbycusis
Amount £35,000 (GBP)
Organisation Age UK 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2010 
End 12/2013
 
Description Deafness Research UK PhD Studentship to study Jaundice
Amount £6,000 (GBP)
Organisation Action on Hearing Loss 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Wellcome Trust Knockout Mouse Resource Committee: Kv2.2 KO
Amount £15,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Wellcome Trust Project Grant (Synaptic transmission in migraine transgenic animal models)
Amount £296,102 (GBP)
Funding ID 084636 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start  
End 12/2011
 
Title Environmental control for in vitro tissue 
Description Development of an organotypic tissue culture method applicable to studies of neuronal homeostasis in the brainstem. 
Type Of Material Technology assay or reagent 
Year Produced 2008 
Provided To Others? Yes  
Impact Some interest from MRC-T and local companies, but no commercial contracts 
 
Description Modelling of neuronal function and dysfunction 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution We conducted experiments on AMPA glutamate receptors in the auditory brainstem. Our collaborators built and refined a kinetic model to explain the temperature dependence observed in our experiments.
Collaborator Contribution It has allowed us to develop increased collaboration between experimentalists and engineers.
Impact A paper Multidisciplinary, computational neurosciecne and experimental neuroscience Modelling of nitric oxide volume transmission. Published in Neuron.
Start Year 2006
 
Description Modelling of neuronal function and dysfunction 
Organisation University of Stirling
Country United Kingdom 
Sector Academic/University 
PI Contribution We conducted experiments on AMPA glutamate receptors in the auditory brainstem. Our collaborators built and refined a kinetic model to explain the temperature dependence observed in our experiments.
Collaborator Contribution It has allowed us to develop increased collaboration between experimentalists and engineers.
Impact A paper Multidisciplinary, computational neurosciecne and experimental neuroscience Modelling of nitric oxide volume transmission. Published in Neuron.
Start Year 2006
 
Description Press release: A role for nitric oxide in the brain? 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Press release by PhD students

Several Newspaper articles were written. Some intersting letters.
On BBC web site
Year(s) Of Engagement Activity 2008,2009
 
Description School visits Leicestershire: Lectures on hearing and the brain 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact Lectues and discussions with teenage students on the ear, hearing and brain function. Includes participation, science as a job and the importance of animals in medical research and human disease

Good feeback, but no epiphany (ies)
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2014,2015