Axonal transport dysfunctions in neurodegenerative 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 global disorders, prompting the necessity for a step-change in treatment strategies to fight these pathologies.
In this view, we are investigating ALS and CMT as disease paradigms to identify new, common targets for pharmacological intervention in these devastating pathologies. Recently, we uncovered alterations in axonal transport of several cytoplasmic organelles, such as mitochondria and signalling endosomes, at pre-symptomatic stages of ALS 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, our main goal is identifying novel signalling nodes that modulate axonal transport in healthy and diseased neurons. This will allow us to test the hypothesis that counteracting axonal transport deficits observed in ALS, CMT and other neurodegenerative diseases, represents a novel, effective therapeutic strategy towards treating these pathologies.

Giampietro Schiavo est invité par Chiara Scaramuzzino.