Axonal transport and neurological disease

Abstract

Axonal transport is the process whereby motor proteins actively navigate microtubules to deliver diverse cargoes, such as organelles, from one end of the axon to the other, and is widely regarded as essential for nerve development, function and survival.Mutations in genes encoding key components of the transport machinery, including motor proteins, motor adaptors and microtubules, have been discovered to cause neurological disease.Moreover, disruptions in axonal cargo trafficking have been extensively reported across a wide range of nervous system disorders. However, whether these impairments have a major causative role in, are contributing to, or are simply a consequence of neuronal degeneration remains unclear. Thus, the fundamental relevance of defective trafficking along axons to nerve dysfunction and pathology is often debated. In this article, we review the latest evidence emerging from human and in vivo studies on whether perturbations in axonal transport are indeed integral to the pathogenesis of neurological disease.

Ultrastructure of the axonal periodic scaffold reveals a braid-like organization of actin rings

“…Rings made of long intertwined filaments are likely to be stiffer than bundled short filaments, hence could form the rigid part of a flexible and resistant scaffold when linked by elastic spectrins (Zhang et al, 2017), explaining the role of the MPS in the mechanical resistance of axons (Krieg et al, 2017). Beyond shedding light on the molecular underlaying of the MPS function, the ultrastructural insights obtained here could help understand its potential dysfunctions in neurodegenerative diseases, where the axonal integrity is often affected first (Encalada and Goldstein, 2014;Sleigh et al, 2019).…”

JIP3 links lysosome transport to regulation of multiple components of the axonal cytoskeleton

“…Axons in particular stand out due to their length which requires both long-range transport for delivery of cargoes to and from distant locations combined with mechanisms to ensure structural integrity (Hammarlund et al, 2007;Lorenzo et al, 2019;Maday et al, 2014). These challenges create unique vulnerabilities that are reflected in the numerous neurodevelopmental and neurodegenerative diseases that arise due to defects in axonal transport and maintenance (Coleman and Hoke, 2020;Millecamps and Julien, 2013;Sleigh et al, 2019). The unique morphology and functions of axons requires specialized organization of multiple cytoskeletal components.…”

Loss of BICD2 in muscle drives motor neuron loss in a developmental form of spinal muscular atrophy

“…Motor neurons have extremely long axons, which make them preferentially susceptible to deficits in axonal transport (Sleigh et al, 2019). It has long been thought that mutations in BICD2 and DYNC1H1 impair axonal transport leading to motor neuron degeneration.…”