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.
Highlights
Signalling endosomes are responsible for the trafficking and distal signalling of activated growth factor receptors in all cell types
We screened a library of kinase inhibitors and identified insulin-like growth factor 1 receptor (IGF1R) as a regulator of the retrograde transport of signalling endosomes
A kinase inhibitor screen reveals a novel modulator of retrograde axonal transport To identify novel modulators of axonal transport, we tested a smallmolecule kinase inhibitor library, using the accumulation of the axotoxic binding fragment of tetanus toxin (HcT) and an antibody directed against the extracellular domain of the p75 neurotrophin receptor (a-p75NTR) in the soma, as a biological readout of axonal transport [12]
Summary
Signalling endosomes are responsible for the trafficking and distal signalling of activated growth factor receptors in all cell types. The long-range retrograde axonal transport of signalling endosomes containing neurotrophins is vital for synaptic plasticity, axon growth and nerve repair [1]. The spatial distribution and trafficking of these organelles, together with mitochondria, RNA granules and lysosomes, is vital for neuronal maintenance and survival. Perturbations in these processes are associated with neurodevelopmental and neurodegenerative diseases [2]. Deficits in the axonal transport of signalling endosomes have been detected in several animal models of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease and Huntington’s disease [3,4,5,6]. Since the molecular determinants of these deficits are currently unknown, it is important to elucidate the mechanisms regulating the trafficking of these organelles
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