IGF1R regulates retrograde axonal transport of signalling endosomes in motor neurons. (7th February 2020)

• Record Type: Journal Article
• Authors: Fellows, Alexander D; Rhymes, Elena R; Gibbs, Katherine L; Greensmith, Linda; Schiavo, Giampietro
• Is Part Of: EMBO reports. Volume 21:Number 3(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-02-07
• Subjects: axonal transport -- cytoplasmic dynein -- IGF1R -- signalling endosome -- tetanus toxin; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201949129
• Languages: English
• ISSNs: 1469-221X

Abstract

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. Synopsis: IGF1R regulates axonal retrograde transport of signalling endosomes by altering the local translation of the motor adaptor BICD1. Inhibition or knockdown of IGF1R leads to an increase in retrograde velocity of signalling endosomes in the axon. This effect is mediated by decreased Akt activation. IGF1R inhibition leads to an increase in the expression of the dynein adaptor BICD1 in the axon. Abstract : IGF1R regulates axonal retrograde transport of signalling endosomes by altering the local translation of the motor adaptor BICD1.