Mouse Models of Neurodegenerative Diseases Laboratory (MMON)
Lead Research Organisation:
MRC Mammalian Genetics Unit
Abstract
Neurodegeneration is defined by loss of specific types of neurons in the brain, spinal cord, or peripheral nerves, occurring in disorders including motor neuron disease and dementia, which we study in this programme. These diseases afflict millions worldwide, are a leading cause of premature death globally, and have devastating social and personal costs to those affected and those who are close to them. Currently we have at best very limited therapeutic options for most neurodegenerative disorders, and cures for none of them.
We need to better understand the onset and progression of these diseases in order to find effective therapies, but critical early disease mechanisms are difficult to study in human patients due to the inaccessibility of the human central nervous system in living patients, and because the neurodegenerative process starts many years before symptom onset. Therefore, we use mice as a model system, and despite 75 million years of evolution separating mouse and humans, we share much the same biology and genetics. In particular, genes that cause familial forms of neurodegeneration are present in both mice and humans and typically share the same function.
By introducing human disease-causing mutations into mice using the latest genome engineering technologies (including CRISR/Cas9), we can model the pathological changes that these mutations cause, including for example, mutations that cause the encoding protein to aggregate leading to neuronal toxicity. Furthermore, we are now humanising whole genes, not just small mutations, to allow improved relevance for human physiology and improved models for therapeutic testing.
We need to better understand the onset and progression of these diseases in order to find effective therapies, but critical early disease mechanisms are difficult to study in human patients due to the inaccessibility of the human central nervous system in living patients, and because the neurodegenerative process starts many years before symptom onset. Therefore, we use mice as a model system, and despite 75 million years of evolution separating mouse and humans, we share much the same biology and genetics. In particular, genes that cause familial forms of neurodegeneration are present in both mice and humans and typically share the same function.
By introducing human disease-causing mutations into mice using the latest genome engineering technologies (including CRISR/Cas9), we can model the pathological changes that these mutations cause, including for example, mutations that cause the encoding protein to aggregate leading to neuronal toxicity. Furthermore, we are now humanising whole genes, not just small mutations, to allow improved relevance for human physiology and improved models for therapeutic testing.
Technical Summary
Neurodegenerative disease encompasses a wide range of disorders afflicting the central and peripheral nervous systems that embody a major unmet biomedical need. There are very limited treatments, and no cures, for most of these diseases, including amyotrophic lateral sclerosis (ALS) and dementia, in which we have a principle interest. The key aims for this programme are (1) to engineer and characterise bespoke models of neurodegeneration and (2) to utilise these and existing models to understand disease pathomechanisms that may lead to new avenues for treatments.
Toward these goals we employ a number of different strategies and genetic tools. Our most straight-forward approach is to make use of the unprecedented range of mouse models available from global collaborations such as the International Knockout Mouse Consortium (IKMC). He we aim to understand the normal function of genes associated with neurodegeneration and neuronal function. We also make use of N-ethyl-N-nitrosourea (ENU) mutant mouse repositories to study point mutations in neurodegenerative disease genes (e.g. ALS genes encoding TDP43 and SOD1).
Our most refined approach involves engineering and studying a new generation of ‘humanised’ knock-in (KI) animals, in which a mouse gene of interest (or specific regions of a mouse gene) is replaced with the orthologous human sequence (e.g. our hFUS and hSOD1 mice). CRISPR/Cas9 technology allows us to additionally introduce any number of human pathogenic mutations to study. The reasons for humanising at the DNA level are so that mouse models express physiological levels of pathogenic genes and proteins analogous to those found in people – with the human splice isoforms and with human protein biochemistry that can be critical for disease pathogenesis. Currently, the most widely used neurodegenerative disease models are transgenic animals that greatly overexpress human pathogenic genes (e.g. SOD1-G93A mice, a widely used ALS model), leading to rapid neurodegeneration (in contrast to humans and KI mice); however, unpicking the effects of overexpression from physiologically relevant pathological changes is difficult in these models. KI models (and similar ‘endogenous’ mutants such as ENU models) develop slowly progressive neurodegenerative disease and thus provide systems for understanding critical early-stage disease mechanisms and biomarkers. Finally, in therapeutic terms, humanised KI models will also allow testing of treatments that target the human transcript or human protein, with potentially better translatability to human patients.
Toward these goals we employ a number of different strategies and genetic tools. Our most straight-forward approach is to make use of the unprecedented range of mouse models available from global collaborations such as the International Knockout Mouse Consortium (IKMC). He we aim to understand the normal function of genes associated with neurodegeneration and neuronal function. We also make use of N-ethyl-N-nitrosourea (ENU) mutant mouse repositories to study point mutations in neurodegenerative disease genes (e.g. ALS genes encoding TDP43 and SOD1).
Our most refined approach involves engineering and studying a new generation of ‘humanised’ knock-in (KI) animals, in which a mouse gene of interest (or specific regions of a mouse gene) is replaced with the orthologous human sequence (e.g. our hFUS and hSOD1 mice). CRISPR/Cas9 technology allows us to additionally introduce any number of human pathogenic mutations to study. The reasons for humanising at the DNA level are so that mouse models express physiological levels of pathogenic genes and proteins analogous to those found in people – with the human splice isoforms and with human protein biochemistry that can be critical for disease pathogenesis. Currently, the most widely used neurodegenerative disease models are transgenic animals that greatly overexpress human pathogenic genes (e.g. SOD1-G93A mice, a widely used ALS model), leading to rapid neurodegeneration (in contrast to humans and KI mice); however, unpicking the effects of overexpression from physiologically relevant pathological changes is difficult in these models. KI models (and similar ‘endogenous’ mutants such as ENU models) develop slowly progressive neurodegenerative disease and thus provide systems for understanding critical early-stage disease mechanisms and biomarkers. Finally, in therapeutic terms, humanised KI models will also allow testing of treatments that target the human transcript or human protein, with potentially better translatability to human patients.
Publications

De Giorgio F
(2019)
Transgenic and physiological mouse models give insights into different aspects of amyotrophic lateral sclerosis.
in Disease models & mechanisms

Devoy A
(2017)
Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in 'FUSDelta14' knockin mice.
in Brain : a journal of neurology

Fisher EMC
(2019)
Mouse models of neurodegeneration: Know your question, know your mouse.
in Science translational medicine

Fratta P
(2018)
Mice with endogenous TDP-43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis.
in The EMBO journal

Nair RR
(2019)
Uses for humanised mouse models in precision medicine for neurodegenerative disease.
in Mammalian genome : official journal of the International Mammalian Genome Society

Sivakumar P
(2018)
TDP-43 mutations increase HNRNP A1-7B through gain of splicing function.
in Brain : a journal of neurology

Zhu F
(2019)
Humanising the mouse genome piece by piece.
in Nature communications
Description | Two PhD studentships from internal funding MRC Harwell |
Amount | £120,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2019 |
End | 08/2022 |
Title | A new mouse model of motor neuron degeneration (FUS ALS) |
Description | A new genetically engineered mouse model of FUS ALS |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | Several labs now working with this model |
Title | Two new humanised FUS mutant strains P525L and Q519Ifs |
Description | Fully humanised FUS gene, wildtype, onto which we have added the P525L mutation and, separately in a second strain of mouse, the Q519Ifs mutation, to try to more faithfully models human FUS motor neuron disease/amyotrophic lateral sclerosis. |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | These mice have been presented at meetings, they are freely available, but we have not yet published on them. |
Title | new humanised SOD1 mouse |
Description | A new Humanised mouse model with the human SOD1 gene; this is a wildtype control for when we go forward to put in human amyotrophic lateral sclerosis mutations into SOD1. |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | This mouse is freely available and has been presented at meetings, but we have not yet published on it. |
Title | Engineered mouse FUS humanised ES cells. |
Description | Mouse cell line that we may analyse rather than working with whole animals, thus helps with aims of NC3Rs. |
Type Of Material | Data analysis technique |
Provided To Others? | No |
Impact | None yet. |
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 | Abraham Acevedo Arozena |
Organisation | Hospital Universitario Insular de Gran Canaria |
Department | La Fundación Canaria Instituto de Investigación Sanitaria de Canarias |
Country | Spain |
Sector | Public |
PI Contribution | PhD student time and effort to develop a new mouse model |
Collaborator Contribution | PhD supervision, DNA analysis, breeding and phenotypic analysis of a cohort of mice. |
Impact | Posters at meetings |
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 | Labs at UCL for bespoke mouse models of neurodegeneration |
Organisation | University College London |
Department | Department of Neuroscience, Physiology and Pharmacology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Genome engineering expertise |
Collaborator Contribution | In depth knowledge of specific forms of neurodegeneration Fratta, Isaacs, Greensmith, Schiavo, Wiseman. |
Impact | None 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 | 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 |
Title | Antibody for FUS Delta 14 disease epitope. |
Description | A disease specific antibody for our FUS Delta14 mouse model of motor neuron disease/amyotrophic lateral sclerosis. |
IP Reference | |
Protection | Protection not required |
Year Protection Granted | 2017 |
Licensed | Yes |
Impact | Antibody for FUS Delta 14 sent out for academic use. |
Description | DS special interest group |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | Wiseman F, LonDownS Consortium (2018) Understanding Down syndrome using Alzheimer's mouse models. Dementia in intellectual disabilities, Special Interest Group Meeting, London, London UK. Talk to mix of medical and other professionals working with peoplewith Down syndrome. |
Year(s) Of Engagement Activity | 2018 |
Description | Edgar talk to Parkinson's patients at Open Day |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Open day at MRC Harwell; PI gave a talk to Parkinson's disease patients and carers. |
Year(s) Of Engagement Activity | 2017 |
Description | Interviewed on BBC Radio 4 for 'The Life Scientific' |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Interviewed by Professor Jim Al-Khalili for a BBC Radio 4 broadcast on the 'Life Scientific'. |
Year(s) Of Engagement Activity | 2019 |
Description | New Scientist Live 2018 MRC Harwell |
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 | New Scientist Live 2018, a public engagement activity for various disciplines in science, on 21 September 2018 |
Year(s) Of Engagement Activity | 2018 |
Description | Research seminar given at Inaugural ALS Symposium, Queen Square 2019, and in Umea, Sweden, and in Yeditepe University, Turkey 2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Three seminars given in UK, Turkey, Sweden, to specialist audiences of researchers, on the disease ALS. One outcome was collaboration and grant writing with the group of expert biochemists in Sweden. |
Year(s) Of Engagement Activity | 2019 |
Description | UCL Postgraduate symposium poster |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | De Giorgio A, Devoy A, Milioto C, Zhu F, MacKenzie K, Acevedo Arozena A, Fisher EMC (2018) Humanising the mouse Tardbp gene. UCL Sixth Annual Postgraduate Research Symposium, London, UK Poster presented to postgraduates outside field. |
Year(s) Of Engagement Activity | 2018 |