New mouse models for tackling motor neuron disease and other neurodegenerative disorders.

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This application is for a 4-year research project to create four new valuable mouse models in which to study neurodegeneration, with a long term view to finding therapeutics. These mouse strains complement and are different from existing models. During this award we will make the mice plus control strains, carry out initial ?clinical? analysis, and will make all the mice freely available to all other interested researchers. Motor neuron diseases (MNDs) are relatively common (in UK 1 in 400 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 (ALS) is a disease of mid-life that has a lifetime risk of up to 1 in 600. These diseases progress inexorably to paralysis and death and we have no treatments that improve quality of life or lifespan of sufferers. MNDs have a genetic component but for ALS only one major effect causative gene, SOD1 has been found (in 1993) and we still have no idea why the mutant form of the protein kills neurons. Recently a protein called TDP43 was identified which aggregates abnormally in the nerve cells of people suffering from ALS and in 2008 rare families have been identified who succumb to ALS with death in mid-life, because they have mutations in the TDP43 gene. TDP43 protein abnormalities have also been found in frontotemporal dementia (the most common form of dementia after Alzheimer?s disease), and Parkinson?s disease, Pick?s disease and other forms of neurodegeneration.Once a human mutant gene such as SOD1 or TDP43 has been identified, the next step is to genetically alter mice so that they recapitulate the human disease and we can study the pathological processes leading to illness and death. SOD1 transgenic mice have been tremendously helpful in understanding ALS, but have disadvantages. Currently no TDP43 mouse models exist. We want to create two new strains of mice, using newer technologies, which more closely model ALS in humans. These mice will be better for understanding human disease, for finding early ?biomarkers? of disease, and for trialling new therapies because they more closely replicate what is happening in humans. We will make the mice freely available to all researchers, without ties, by distributing them in the major mutant mouse repositories in Europe and USA for sending out to all research labs.