Fellows, Alexander Douglas; (2019) Investigating the role of the insulin-like growth factor receptor (IGF1R) on axonal transport as a target for pharmacological intervention in Amyotrophic Lateral Sclerosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Signalling endosomes are essential for neuronal survival, trafficking of essential ligand receptor complexes and propagating the distal signalling of activated growth receptors. Deficits in their transport have been linked to multiple neurodegenerative diseases, therefore it is essential that we understand the mechanisms controlling their transport in both healthy and disease phenotypes. In this study we describe a new modulator of signalling endosome trafficking, the insulin-like growth factor 1 receptor (IGF1R). We show that IGF1R inhibition increases the velocity of signalling endosomes both in vitro and in vivo. This effect is specific to signalling endosomes, since IGF1R inhibition does not alter the trafficking of mitochondria or lysosomes. We find that this change in trafficking is likely to be linked to the dynein adaptor bicaudal-D1 (BICD1), as upon IGF1R inhibition we see substantial increase in the de novo synthesis of this protein in the axon of motor neurons, without any significant alteration of the microtubule cytoskeleton or the levels of cytoplasmic dynein. Finally, we demonstrate that IGF1R inhibition can improve the deficits found in signalling endosomes transport in the SOD1G93A mouse model of amyotrophic lateral sclerosis (ALS). These data suggest that IGF1R inhibition could be a viable therapeutic target for ALS.

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