Disruption of axonal transport in neurodegeneration

Abstract

Neurons are markedly compartmentalized, which makes them reliant on axonal transport to maintain their health. Axonal transport is important for anterograde delivery of newly synthesized macromolecules and organelles from the cell body to the synapse and for the retrograde delivery of signaling endosomes and autophagosomes for degradation. Dysregulation of axonal transport occurs early in neurodegenerative diseases and plays a key role in axonal degeneration. Here, we provide an overview of mechanisms for regulation of axonal transport; discuss how these mechanisms are disrupted in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, hereditary spastic paraplegia, amyotrophic lateral sclerosis, and Charcot-Marie-Tooth disease; and discuss therapeutic approaches targeting axonal transport.

Figure 1. Axonal transport in neurons.

Neurons are compartmentalized, with long axons. Delivery of organelles in the axon is performed via the motor proteins kinesin and dynein, which carry cargoes along microtubule tracks. Kinesin is responsible for anterograde transport of organelles, from the soma to the presynaptic terminal. Dynein is responsible for retrograde transport of organelles from the presynaptic terminal to the cell body. Dynein processivity is enhanced via binding to the essential cofactor dynactin and a cargo adaptor.

Figure 2. Regulation of axonal transport.

Axonal transport is regulated via phosphotransferase activity. The kinases GSK3β and casein kinase 2 (CK2) inhibit anterograde axonal transport via phosphorylation of kinesin light chains, while the kinases JNK and p38 MAPK (p38) inhibit anterograde axonal transport via phosphorylation of kinesin heavy chains. GSK3β phosphorylates dynein intermediate chains to inhibit retrograde axonal transport, while CK1 phosphorylates dynein intermediate chains to activate retrograde axonal transport. Inset: Posttranslational modifications of microtubules. Microtubules are composed of α- and β-tubulin. α-Tubulin can be modified via acetylation, detyrosination, and polyglutamylation, while β-tubulin is modified by polyglutamylation.

Figure 3. Dysregulation of axonal transport in neurodegenerative diseases.

Neurodegenerative diseases disrupt axonal transport via multiple mechanisms, including motor protein regulation via phosphorylation, adaptor binding, and impaired microtubule regulation. Each neurodegenerative disease has different altered patterns of axonal transport disruption, which may contribute to disease specificity. AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; HD, Huntington’s disease; HSP, hereditary spastic paraplegia; IPN, inherited peripheral neuropathy; PD, Parkinson’s disease; PS, Perry syndrome.