The genetics of axonal transport and axonal transport disorders

Abstract

Neurons are specialized cells with a complex architecture that includes elaborate dendritic branches and a long, narrow axon that extends from the cell body to the synaptic terminal. The organized transport of essential biological materials throughout the neuron is required to support its growth, function, and viability. In this review, we focus on insights that have emerged from the genetic analysis of long-distance axonal transport between the cell body and the synaptic terminal. We also discuss recent genetic evidence that supports the hypothesis that disruptions in axonal transport may cause or dramatically contribute to neurodegenerative diseases.

Figure 1. Cytoplasmic Dynein and Kinesin Power Axonal Transport

Schematic diagram of the microtubule motor proteins cytoplasmic dynein and kinesin. Cytoplasmic dynein transports cargo in the retrograde direction toward the minus ends of microtubules whereas kinesin transports cargo in the anterograde direction toward the plus ends. Cytoplasmic dynein is a large multimeric protein complex comprising two heavy chain subunits (red) that possess microtubule binding and ATPase activity, two intermediate chains (yellow), two light intermediate chains (indigo), and an assortment of light chains (light pink, green, orange) (reviewed in [7]). Dynactin, a large multisubunit protein complex of comparable size to cytoplasmic dynein, is proposed to link the dynein motor to cargo and/or increases its processivity. The largest dynactin subunit, p150^Glued (turquoise), forms an elongated dimer that interacts with the dynein intermediate chain and binds to microtubules via a highly conserved CAP-Gly motif at the tip of globular heads. The dynactin subunit p50 (dark pink) occupies a central position linking p150^Glued to cargo. The conventional kinesin holoenzyme, also known as kinesin-1, is a heterotetramer comprising two Khc subunits (red) with microtubule binding and ATPase domains, a central coiled stalk, and a tail domain that interacts with two Klc subunits (green). Klcs may mediate cargo-binding via an intermediate scaffold protein (blue) that binds a cargo transmembrane protein (yellow).