Neurodegeneration

Lead Research Organisation: MRC Mammalian Genetics Unit

Abstract

Our major aim is to identify new genes or genetic pathways involved in neurodegeneration and try to understand how these genetic mutations lead to disease using mouse models.
Once a human genetic mutation is identified that is causative for a disorder, the next step in most investigations of disease mechanisms (and therefore in developing therapeutics) is to make mouse models of the genetic disorder, such that we can then investigate every stage of pathogenesis in all tissues. This is critically important for neurodegeneration, where interactions between different neuronal populations and other cells in the brain and spinal cord cannot be recapitulated in vitro.
We focus our work mainly on Amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). They are both fatal neurodegenerative disorders for which no major treatments exist. The focus of our work is twofold. First, we work on new disease causative genes identified by others and develop new mouse models carrying mutations on those genes with the ultimate aim of understanding how these mutations lead to neurodegeneration at the cellular and molecular level. Second, we identify new genes involved in neurodegeneration in the mouse by using mutagenesis. The mutagenesis consist of mutating genes in the mouse and then study the mutant mice over time for any neurodegenerative disease symptoms, such as muscle weakness or motor disturbances such as tremors or gait abnormalities.
All new mouse models identified are made freely available to the scientific community.

Technical Summary

Our major aim is to identify and elaborate new genetic pathways involved in neurodegeneration using disease mouse models. In particular, we focus our work on two major neurodegenerative disorders: Huntington’s disease (HD) and Amyotrophic lateral sclerosis (ALS). Despite intense research focus on HD and ALS, they both remain incurable, and the only available treatment licensed for ALS, Riluzole, has limited therapeutic benefits. Although both disorders are very different in their genetics, they are both fatal and exemplify the need for a deeper understanding of disease pathogenesis as the base on which to build the search for therapeutic intervention.
Mouse models are critical in our current understanding of disease processes, including neurodegeneration. The focus of our programme is to elaborate on disease pathogenesis by studying neurodegeneration mouse models. We work with both established neurodegeneration mouse models as well as generating our own new mouse models, making them immediately available to the research community. We uncover new genes and mechanisms leading to neurodegeneration by means of two major methodologies: First, the generation of new disease mouse models carrying point mutations in known neurodegenerative causative genes, their behavioural characterisation and the subsequent elucidation of the molecular mechanisms leading to disease. We are currently focussing on ALS genes using this approach, and have uncovered new ALS mouse models carrying point mutations in Sod1 and Tardbp (the gene encoding TDP43). Second, the identification of new genes involved in neurodegeneration by means of ENU mutagenesis forward genetics screening. The screening pipelines used include modifier screens over well established disease mouse models (both HD and ALS models) as well as the identification of new neurodegenerative genes through the Harwell ENU ageing screen pipeline.
Our genetic work is set in the context of our key links into other leading UK laboratories bringing genetic, biochemical and cell biological studies to bear. The new mouse models provided, together with the new disease pathways identified would be valuable tools in the further elucidation of neurodegeneration pathophysiology by us and others.

Publications

10 25 50
 
Description Charity visit for the Concordat on Openness on Animal Research
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Motor Neurone Disease Association PhD studentship
Amount £88,690 (GBP)
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2015 
End 09/2018
 
Description Motor Neurone Disease Association Studentship
Amount £112,690 (GBP)
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2014 
End 08/2017
 
Title mouse model for myotonia and periodic paralysis 
Description A new mouse model of myotonia and periodic paralysis carrying a novel point mutation in the gene Scn4a 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2014 
Provided To Others? Yes  
Impact Just published 
 
Description BBC website 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact BBC website documentary on mouse research

Not aware of any impact
Year(s) Of Engagement Activity 2014
URL http://www.bbc.co.uk/news/health-26255305
 
Description Cheltenham Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Participation, via a member of the group (Dr Alison Landman) on the MRC Harwell stand and the Cheltenham Science Festival

Good response from general members of the public
Year(s) Of Engagement Activity 2014
 
Description MRC careers workshop 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Talk by Silvia Corrochano, a member of the work, on the 2014 Science career workshop by the MRC

MRC headoffice made aware of the difficulties to make the transition between post-doctoral researcher and junior group leader
Year(s) Of Engagement Activity 2014
 
Description Oxfordshire Science Festival-Bonn Square, Oxford 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact MRC stand on Oxfordshire Science Festival-Bonn Square, Oxford: Brain and neurodegeneration

Increase interest from members of the public, particulary children, on research into neurodegeneration
Year(s) Of Engagement Activity 2014
 
Description Seminar Madrid, SIlvia 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Seminar in Madrid on our work on Huntington's disease modifiers

To inform of our research results internationally and to establish new collaborators
Year(s) Of Engagement Activity 2014
 
Description Seminar Sussex University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Neuroscience Department seminar

Collaborative work with Dr Majid Hafezparast
Year(s) Of Engagement Activity 2014