Next invited talk:

Giampietro Schiavo

Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, WC1N 3BG

UK Dementia Research Institute, University College London, London, WC1E 6BT, UK

Restoring axonal transport in neurological diseases

The molecular mechanisms causing neuronal death in many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Charcot Marie Tooth (CMT) 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 disorders, prompting the necessity for a step-change in treatment strategies to fight these pathologies.

In this view, we are investigating ALS/FTD and CMT as disease paradigms to identify new targets for pharmacological intervention in these devastating pathologies. Recently, we uncovered alterations in axonal transport of several cytoplasmic organelles, such as mitochondria, secretory granules and signalling endosomes, at pre-symptomatic stages of ALS/FTD and CMT 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. 

In light of these promising results, we identified brain derived growth factor (BDNF) and its receptor TrkB, insulin-like growth factor 1 receptor (IGF1R), p38 MAPKalpha, and ERK1/2 as key signalling nodes modulating axonal transport in healthy and diseased neurons. This has allowed us to test the hypothesis that counteracting axonal transport deficits observed in ALS/FTD, CMT and other neurodegenerative diseases represents a novel, effective therapeutic strategy towards treating these pathologies.