Identification of modifiers of the axonal transport pathway in health and disease

The molecular mechanisms causing neuronal death in many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease, are poorly understood. The key consequence of our incomplete understanding of disease pathogenesis is that there is a complete dearth of effective symptomatic treatments for these widespread global disorders, prompting the necessity for a step-change in treatment strategies to fight these pathologies. In this view, we are investigating ALS as a disease paradigm to identify new, common targets for pharmacological intervention in these devastating pathologies. In work leading to this proposal, we uncovered alterations in axonal transport of several cytoplasmic organelles at pre-symptomatic stages of ALS pathogenesis, suggesting that these impairments may play a causative role in disease onset and progression. Crucially, we have restored axonal transport to physiological levels at early symptomatic stages of disease, thus demonstrating that these pathological changes are fully reversible. Our program of work aims to identify novel signalling nodes that modulate axonal transport in healthy and ALS motor neurons. This will allow us to test the hypothesis that counteracting axonal transport deficits observed in ALS and other neurodegenerative diseases, represents a novel, effective therapeutic strategy towards treating these currently incurable pathologies.