Kinase inhibition and axonal transport deficits in the SOD1G93A mouse model of ALS.

Defective axonal transport of organelles, proteins, mRNA and vesicles is an early feature amyotrophic lateral sclerosis (ALS). Restoration of physiological axonal transport therefore holds promise as a potential therapeutic route. Early and presymptomatic deficits in axonal transport are seen in the SOD1G93A ALS mouse model, both in vitro and in vivo, making this an ideal model to study these deficits, and test potential therapeutics. A screen of kinase inhibitors conducted in the lab identified a number of kinases to target for transport acceleration, including p38MAPK, IGF1R and Ret. Both p38MAPK and IGF1R have been validated as targets, as their inhibition is able to rescue SOD1G93A transport deficits. The aim of this project is to validate the third hit identified in the kinase inhibitor screen, Ret. Ret is a tyrosine kinase receptor, whose ligands include the glial-cell line derived neurotrophic factor (GDNF), a key neurotrophic factor for motor neuron homeostasis. This project explores the levels, activation and localisation of Ret in WT vs SOD1G93A primary motor neurons, and assesses the effect of Ret inhibition on retrograde axonal transport. I will also investigate the mechanisms underlying the in vitro SOD1G93A axonal transport deficit, and explore the downstream effects of IGF1R and RET inhibition, to identify any common players that could provide more specific therapeutic targets for inhibition.