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.
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.
Organisations
- Medical Research Council (Lead Research Organisation)
- University College London, United Kingdom (Collaboration)
- University of Padova (Collaboration)
- MRC Harwell, United Kingdom (Collaboration)
- University of Cambridge (Collaboration)
- University of Sussex, United Kingdom (Collaboration)
- Northwestern University (Collaboration)
- University of Queensland, Australia (Collaboration)
- International Centre for Genetic Engineering and Biotechnology (Collaboration)
Publications

Acevedo-Arozena A
(2011)
A comprehensive assessment of the SOD1G93A low-copy transgenic mouse, which models human amyotrophic lateral sclerosis.
in Disease models & mechanisms

Achilli F
(2009)
An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy.
in Disease models & mechanisms

Ateh DD
(2008)
Dynein-dynactin complex subunits are differentially localized in brain and spinal cord, with selective involvement in pathological features of neurodegenerative disease.
in Neuropathology and applied neurobiology

Banks GT
(2008)
Cytoplasmic dynein could be key to understanding neurodegeneration.
in Genome biology

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


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

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

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

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 | £82,606 (GBP) |
Organisation | Motor Neurone Disease Association (MND) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2008 |
End | 10/2011 |
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 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 | Charity/Non Profit |
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 | 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 | 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 | Brain Visiting Lecturer |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | This was a one week event during which professor Dame Pamela Shaw, Sheffield University, had discussions with various research groups as well as junior clinicians, PhD students and medical students. It ended with a Mini-symposium entitled Generic Disease Mechanisms in Motor Neurone Disease and other Neurodegenerative Disorders. National and international speakers were invited to these events to deliver seminars on their research and current topics in the field. Keynote speaker was professor Dame Pamela Shaw from Sheffield University. This event was attended by over 130 delegates and involved 10 speakers as well as a number of poster presentations. |
Year(s) Of Engagement Activity | 2017 |
Description | Interview - BBC Sussex, Surry and Kent for 'The ABC of MND' |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | This interview was conducted by a BBC reporter as part of The ABC of MND run by BBC Sussex, Surry and Kent to enhance awareness about MND. It included interviews with patients, carers, professional practitioners, MND Associations representatives, clinicians and myself as a scientist in region working on MND. |
Year(s) Of Engagement Activity | 2008 |
URL | https://www.bbc.co.uk/programmes/articles/1fc16gdxK1QYYxLWqvzf2Ms/the-abc-of-mnd |
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 | Sussex MND Care & Research Network Stakeholder Launch |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | This event was for the launch of Sussex MND Care and Research Network, in which the objectives of the Network were presented and discussed. As part of this event I outlined our research motor neurone disease in a powerpoint presentation, which sparked interest in our research as evident by a good number of questions about its implications in treatment of the disease. |
Year(s) Of Engagement Activity | 2017 |
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 |