Anterograde Axonal Transport in Neuronal Homeostasis and Disease

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.

Keywords: axon growth; intracellular transport; kinesin; liquid phase separation; local translation; neurodegeneration; synaptogenesis.

Figure 1

(A) Microtubule (MT)-based transport machinery. Schematic representation showing how different molecular motors move along MTs toward MT plus-end (kinesins) or MT minus-end (dynein). Kinesins and dyneins motor domain bind to MT through their globular head domains which hydrolyze ATP during movement. Anterograde or retrograde cargoes bind to the tail domain of the motor either directly or through light/intermediate chains or adaptors. (B) Kinesin-mediated anterograde transport during axon elongation and synaptogenesis. Anterograde microtubule-dependent movements of membranous organelles and RNA granules are supported by various plus-end-directed kinesin motors. Organelles such as mitochondria, vesicles, RNA are transported from the soma toward axon tip during axonal growth and synapse formation. In the absence of motor activity, some kinesins also contribute to MT depolymerization during growth cone retraction.

Figure 2

Schematic representation highlighting the association between RNA granule transport, neurofilaments (NFs), mitochondria, and kinesin motors with selected neuronal degenerative diseases. In the case of mitochondria defects, the mutated proteins underlying neurodegeneration are listed.