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IGF1R regulates retrograde axonal transport of signalling endosomes in motor neurons

Fellows, AD; Rhymes, ER; Gibbs, KL; Greensmith, L; Schiavo, G; (2020) IGF1R regulates retrograde axonal transport of signalling endosomes in motor neurons. EMBO Reports , Article e49129. 10.15252/embr.201949129. (In press). Green open access

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Abstract

Signalling endosomes are essential for trafficking of activated ligand–receptor complexes and their distal signalling, ultimately leading to neuronal survival. Although deficits in signalling endosome transport have been linked to neurodegeneration, our understanding of the mechanisms controlling this process remains incomplete. Here, 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 in motor neuron axons, both in vitro and in vivo. This effect is specific, since IGF1R inhibition does not alter the axonal transport of mitochondria or lysosomes. Our results suggest that this change in trafficking is linked to the dynein adaptor bicaudal D1 (BICD1), as IGF1R inhibition results in an increase in the de novo synthesis of BICD1 in the axon of motor neurons. Finally, we found that IGF1R inhibition can improve the deficits in signalling endosome transport observed in a mouse model of amyotrophic lateral sclerosis (ALS). Taken together, these findings suggest that IGF1R inhibition may be a new therapeutic target for ALS.

Type: Article
Title: IGF1R regulates retrograde axonal transport of signalling endosomes in motor neurons
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.15252/embr.201949129
Publisher version: https://doi.org/10.15252/embr.201949129
Language: English
Additional information: This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/
Keywords: IGF1R, axonal transport, cytoplasmic dynein, signalling endosome, tetanus toxin
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10091107
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