Bridging the gap: large animal models in neurodegenerative research

The world health organisation has declared neurological disorders as one of the greatest public health risks in the world today. Yet, despite this growing concern, the mechanisms underpinning many of these conditions are still poorly understood. This may in part be due to the seemingly diverse nature of the initiating insults ranging from genetic (such as the Ataxia's and Lysosomal storage disorders) through to protein misfolding and aggregation (i.e. Prions), and those of a predominantly unknown aetiology (i.e. Alzheimer's and Parkinson's disease). However, efforts to elucidate mechanistic regulation are also likely to be hampered because of the complexity of the human nervous system, the apparent selective regional vulnerability and differential degenerative progression. The key to elucidating these aetiologies is determining the regional molecular cascades, which are occurring from the early through to terminal stages of disease progression. Whilst much molecular data have been captured at the end stage of disease from post-mortem analysis in humans, the very early stages of disease are often conspicuously asymptomatic, and even if they were not, repeated sampling from multiple brain regions of "affected" patients and "controls" is neither ethical nor possible. Model systems therefore become fundamental for elucidating the mechanisms governing these complex neurodegenerative conditions. However, finding a model that precisely mimics the human condition can be challenging and expensive. Whilst cellular and invertebrate models are frequently used in neurodegenerative research and have undoubtedly yielded much useful data, the comparatively simplistic nature of these systems makes insights gained from such a stand alone model limited when it comes to translation. Given the recent advances in gene editing technology, the options for novel model generation in higher order species have opened up new and exciting possibilities for the field. In this review, we therefore explain some of the reasons why larger animal models often appear to give a more robust recapitulation of human neurological disorders and why they may be a critical stepping stone for effective therapeutic translation.