Dissecting the processes of motor neuron disease

Lead Research Organisation: Medical Research Council
Department Name: Medical Research Council

Abstract

All four applicants consider the public dissemination of science at all levels, to be paramount, especially for subjects such as genetics and neurobiology. They have all lectured to non-specialists ranging from CEOs of leading utility companies to local school children, and at the Royal Institution to the Science Museum. In addition, for example, EF was a BA Media Fellow and worked for 8 weeks in the BBC World Service, conveying science to an international audience, and still has strong ties to the Association of British Science Writers including judging their 2003 and 2004 ABSW awards. All groups also regularly give talks to the lay public in Patients and Carers groups.

Technical Summary

This Research Grant application is for a 4-year focussed mutagenesis project to create a resource for functionally dissecting the mechanism of mutant SOD1 action and neurodegeneration.

Motor neuron diseases (MNDs) are relatively common (1 in 500 death certificates is issued for some form of MND) and can strike at any age ? spinal muscular atrophy is the biggest single genetic killer of children world-wide, whereas amyotrophic lateral sclerosis is a disease of mid-life (40s, 50s). These disease progress inexorably to paralysis and death and we have no treatments that significantly improve quality of life or lifespan of sufferers. Clearly MNDs have a genetic component and are genetically heterogeneous, however only one major effect causative gene, SOD1 has been found (in 1993) and we still have no idea as to its toxic gain of function. Thus there are 2 key issues in MND research, which are also relevant to basic neurobiology studies of motor neuron function:
1. what is the toxic gain of function of mutant SOD1?
2. what other genes and hence pathways are associated with MN death and dysfunction?

We will attack these questions in an innovative Program that capitalises on the unique combination of the genetics and phenotyping skills of our groups, our existing collaborations with a wide range of scientists and clinicians, and access to one of the world?s premier mouse resources at MRC Harwell. We will set up a SENSITISED-SCREEN to look for genes/pathways that specifically affect the toxic gain of function of mutant SOD1. We will use the resulting set of new mutations as a future resource for us and the MND community for detailed phenotypic and genetic analysis to dissect molecular processes leading us to important cell biological pathways involved in the mutant SOD1 gain of function, ultimately for translation into therapeutic targets.

Publications

10 25 50

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Banks GT (2008) TDP-43 is a culprit in human neurodegeneration, and not just an innocent bystander. in Mammalian genome : official journal of the International Mammalian Genome Society

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Banks GT (2011) Behavioral and other phenotypes in a cytoplasmic Dynein light intermediate chain 1 mutant mouse. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Becker EB (2009) A point mutation in TRPC3 causes abnormal Purkinje cell development and cerebellar ataxia in moonwalker mice. in Proceedings of the National Academy of Sciences of the United States of America

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Bowen S (2007) The phagocytic capacity of neurones. in The European journal of neuroscience

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Bunton-Stasyshyn RK (2015) SOD1 Function and Its Implications for Amyotrophic Lateral Sclerosis Pathology: New and Renascent Themes. in The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry

 
Description MNDA PhD Studentship
Amount £110,000 (GBP)
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 09/2014
 
Description MNDA PhD Studentship
Amount £82,606 (GBP)
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2008 
End 10/2011
 
Description MNDA Research Grant
Amount £254,819 (GBP)
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2009 
End 12/2012
 
Description MNDA Small Grant
Amount £10,000 (GBP)
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2008 
End 12/2008
 
Description NC3Rs PhD studentship
Amount £120,000 (GBP)
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Private
Country United Kingdom
Start 10/2011 
End 09/2014
 
Description PhD studentship MNDA Humanizing the Tardbp (TDP43) locus in the mouse
Amount £88,690 (GBP)
Funding ID Fisher (10/442) 
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2015 
End 11/2018
 
Description Research grant
Amount £80,000 (GBP)
Organisation Thierry Latran Foundation 
Sector Charity/Non Profit
Country France
Start 08/2009 
End 09/2011
 
Title Mouse humanised wildtype FUS model 
Description Humanised genomic wildtype FUS gene in mouse 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2015 
Provided To Others? Yes  
Impact Pending 
 
Title mouse models for fus mnd delta 14 only 
Description Mouse models of motor neuron degeneration, with a specific mutation in the gene FUS (delta 14) 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2014 
Provided To Others? Yes  
Impact Papers pending, and model is basis of two new grant applications (both successful) 
 
Title FUS homozygotes MEFs 
Description Working with a mouse model, an in vivo model, to produce IMMORTILISED cell lines so that we can drop our animal useage. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact Reduced mouse numbers 
 
Description Analysing the metabolome Griffin, Cambridge 
Organisation University of Cambridge
Department Department of Earth Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Access to novel mice and mouse crosses
Collaborator Contribution Analysis of the metabolome including lipidomics
Impact No outputs yet
Start Year 2016
 
Description Analysis of the FUS mouse translatome, Fratta, UCL 
Organisation University College London
Department Marie Curie Palliative Care Research Department
Country United Kingdom 
Sector Academic/University 
PI Contribution contribution of the unique FUS Delta14 mouse model
Collaborator Contribution RiboTagging and ChatCre breeding to pull down polysomes from the Delta14 mouse
Impact Multidisiplinary output. No outcomes yet as just started.
Start Year 2016
 
Description Imaging 
Organisation University College London
Department Centre for Advanced Bioimaging
Country United Kingdom 
Sector Academic/University 
PI Contribution Mouse models
Collaborator Contribution High resolution imaging
Impact Papers, studentships.
Start Year 2006
 
Description Looking at gliosis in neurodegeneration 
Organisation University of Queensland
Country Australia 
Sector Academic/University 
PI Contribution Access to unique mouse models and crosses
Collaborator Contribution Analysis of gliosis and potentially the inflammasome
Impact No outputs yet
Start Year 2017
 
Description MMON 
Organisation MRC Harwell
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration with the Mouse Models of Neurodegeneration lab at MRC Harwell, analysis of homozygous and heterozygous mice
Collaborator Contribution Breeding, inbreeding onto another background, and phenotypic analysis of homozygous and heterozygous mice.
Impact Inbred mice on different backgrounds. Cohorts of mice of different ages, sex-matched with littermate controls, wildtype, heterozygous, homozygous, for phenotypic analysis. Analysis of different phenotypes ranging from behavioural through to physiological.
Start Year 2017
 
Description Physiology of new mouse models of motor neuron disease 
Organisation International Centre for Genetic Engineering and Biotechnology
Country Italy 
Sector Charity/Non Profit 
PI Contribution Contributing new mouse models and personnel.
Collaborator Contribution Physiological analysis of new mouse models of a human disease, and cellular and molecular analysis of these models.
Impact Assessing mouse models for relevance to human disease. Publications pending. This has been and remains an extremely important collaboration for my research.
Start Year 2006
 
Description Physiology of new mouse models of motor neuron disease 
Organisation Northwestern University
Department Ken & Ruth Davee Department of Neurology
Country United States 
Sector Hospitals 
PI Contribution Contributing new mouse models and personnel.
Collaborator Contribution Physiological analysis of new mouse models of a human disease, and cellular and molecular analysis of these models.
Impact Assessing mouse models for relevance to human disease. Publications pending. This has been and remains an extremely important collaboration for my research.
Start Year 2006
 
Description Physiology of new mouse models of motor neuron disease 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution Contributing new mouse models and personnel.
Collaborator Contribution Physiological analysis of new mouse models of a human disease, and cellular and molecular analysis of these models.
Impact Assessing mouse models for relevance to human disease. Publications pending. This has been and remains an extremely important collaboration for my research.
Start Year 2006
 
Description molecular cell biology of neurons 
Organisation University of Sussex
Department School of Life Sciences Sussex
Country United Kingdom 
Sector Academic/University 
PI Contribution supplying mouse resources and cells
Collaborator Contribution expertisei n molecular neurobiology
Impact publications
 
Description studying ribosomal proteins 
Organisation University of Padova
Department Department of Neurosciences
Country Italy 
Sector Hospitals 
PI Contribution Access to a unique mouse model of FUS ALS (Delta14)
Collaborator Contribution Analysis of ribosomal proteins
Impact No outputs yet
Start Year 2017
 
Description Open day for patients 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Talking directly to patients and carers about animal research and how we work with animals to understand motor neuron disease.

Telling patients about the current state of our work.
Year(s) Of Engagement Activity 2012
 
Description Private meeting with major funders 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Supporters
Results and Impact Private meeting to inform major funders of research in motor neuron disease supported by the charity in question.

Maintaining funders enthusiasm and interest and showing value for money.
Year(s) Of Engagement Activity Pre-2006,2012
 
Description lay meeting motor neuron disease association 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Talking with potential funders affected by motor neuron disease, with the Motor Neuron Disease Association.

Believe helped towards contribution made to the Motor Neuron Disease Association.
Year(s) Of Engagement Activity 2006