Analysis of neurodegenerative disorders across multiple species

Neurological disorders affect one in six people globally (neural.org.uk). These conditions are caused by a broad range of factors which ultimately result in the altered form and/or function of the nervous system. The pathology of these conditions can vary greatly in terms of aetiology, age of onset and duration, but collectively they represent a significant drain on the health care system. Due to the nature of these disorders acquisition of samples from patients is rare and unfeasible in pre-symptomatic patients, unless a family member is diagnosed with an inheritable condition forewarning future generations/siblings to the risk. Therefore, in order to progress the understanding of any biological condition a model system is established to allow researchers to gain a better understanding of pathogenesis and the mechanisms involved in disease progression. Moreover, models also provide a platform to identify biomarkers for the condition that could then be used to inform on rates of disease progression and the effectiveness of any potential therapeutic intervention. Importantly, the model must faithfully translate the disease observed in human patients in order to address biological questions and produce efficacious therapeutic targets. Small animal models are commonly used to report on various aspects on neurological conditions providing much of the groundwork to understand the basic disease processes involved. Unfortunately, there is a high failure rate of therapies to translate into effective interventions in human patients when moving straight from the assessment in small animal models in human patients. This is likely (amongst many other factors), due to anatomical disparities in terms of both scale and complexity of the nervous system. It is now becoming widely accepted that a large animal intermediate model system is required to leverage more effective translation of neurological conditions into the clinic. Here I present a body of published work describing my contributions to the field of neurodegenerative research through the analysis of large animal neurological systems. I will 1. summarise the state of the field and requirement for large animal model systems, 2. Discuss the development of specific workflows and considerations which are critical for the analysis of samples from such models. 3. describe our investigations into diseases of large animals which can be used to inform on human conditions (equine grass sickness and ovine scrapie), and 4. Describe the lessons learned from our generation of the first ever CRISPR edited ovine model of a human neurodegenerative condition.