Mouse Models of Neurodegenerative Diseases Laboratory (MMON)

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.

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.