Anterograde Axonal Transport in Neuronal Homeostasis and Disease.

Laurent Guillaud,Marco Terenzio,Miki Otsuki,Sara Emad El-Agamy

doi:10.3389/fnmol.2020.556175

Abstract

Neurons are highly polarized cells with an elongated axon that extends far away from the cell body. To maintain their homeostasis, neurons rely extensively on axonal transport of membranous organelles and other molecular complexes. Axonal transport allows for spatio-temporal activation and modulation of numerous molecular cascades, thus playing a central role in the establishment of neuronal polarity, axonal growth and stabilization, and synapses formation. Anterograde and retrograde axonal transport are supported by various molecular motors, such as kinesins and dynein, and a complex microtubule network. In this review article, we will primarily discuss the molecular mechanisms underlying anterograde axonal transport and its role in neuronal development and maturation, including the establishment of functional synaptic connections. We will then provide an overview of the molecular and cellular perturbations that affect axonal transport and are often associated with axonal degeneration. Lastly, we will relate our current understanding of the role of axonal trafficking concerning anterograde trafficking of mRNA and its involvement in the maintenance of the axonal compartment and disease.

Highlights

From the discovery of kinesin-1 (Vale et al, 1985) and cytoplasmic dynein (Paschal et al, 1987) in the late 20th century and their initial characterization as anterograde and retrograde motors, respectively (Hirokawa et al, 1990, 1991), substantial effort has been made to decipher their role in neuronal development, connectivity, and synaptogenesis
It has been reported that a single cargo could be associated with several motors proteins and the resulting force produced by the ratio between plus-end and minus-end directed motors might determine the final directionality of the movement (Kural et al, 2005; Hendricks et al, 2010), only a few cargoes were addressed in this work and it remains unclear whether these findings extend to other cargoes as well
A novel KIF1Bβ mutation, Y1087C, was identified in connection with CMT2 (Xu et al, 2018). This mutation was shown to impair the binding between KIF1Bβ and the insulin-like growth factor 1 receptor (IGF1R), affecting IGF1R axonal transport, decreasing its exposure on the neuronal surface and negatively impacting Insulin growth factor 1 (IGF-1) signaling, which is essential for neuronal development and survival (Xu et al, 2018)

Summary

Introduction

From the discovery of kinesin-1 (Vale et al, 1985) and cytoplasmic dynein (Paschal et al, 1987) in the late 20th century and their initial characterization as anterograde and retrograde motors, respectively (Hirokawa et al, 1990, 1991), substantial effort has been made to decipher their role in neuronal development, connectivity, and synaptogenesis. Most work regarding the tail domain characterization has been the focus on kinesin-1 (KIF5A/B/C) and kinesin-3 (KIF1A) family members, which are most studied motors responsible for anterograde transport in the axon, and for which a large number of adaptor proteins mediating their binding to a different population of vesicles has been identified (Verhey et al, 2001; Setou et al, 2002; Wang and Schwarz, 2009; Fu and Holzbaur, 2014).

Results

Conclusion