Axon Transport Deficits: Neurodegeneration’s First Sign?
When axonal transport is disrupted, neurodegeneration follows, according to a study in EAE mice
Neurons in the brain need a lot of support in order to survive. Since axons can grow to many times the length of the cell body, they need regular shipments of cargo containing proteins and organelles. To deliver those shipments, neurons rely on a process called axonal transport, by which cargo is carried by motor proteins up and down spindle-like microtubules running the length of the axon.
A kinesin protein walks a cargo along a microtubule filament. From: “Inner Life of the Cell,” ©2006 President and Fellows of Harvard College. Created by Alain Viel, Ph.D., and Robert Lue, Ph.D., in collaboration with XVIVO, LLC, and John Liebler, Lead Animator. Made possible through the generous support of the Howard Hughes Medical Institute's Undergraduate Science Education Program.
When axonal transport is disrupted, neurodegeneration follows. Recently, a team of researchers demonstrated that axonal transport is dysregulated in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). In a study published in the December issue of the journal Neuron, the research team showed that deficits in axonal transport were pervasive but reversible. Their research may also shed light on new approaches to treating progressive multiple sclerosis, for which no medications currently exist (Sorbara et al., 2014).
The researchers used two-photon microscopy, a fluorescence imaging technique that allows researchers to peer into the depths of living tissue. First they found that the transport of mitochondria was significantly slower and subject to many more pauses in the axons of EAE mice, even in normal-appearing cells (0.31 ± 0.03 μm/s in normal, myelinated axons versus 0.49 ± 0.03 μm/s in normal-appearing EAE axons). The researchers linked the pattern of disruption through the density of mitochondria and suggested that it may be the result of both inflammatory and demyelination processes.
The researchers also found that deficits in axonal transport begin before any obvious abnormalities show up in microtubules, the train tracks for axon transport proteins. In other words, the transport disruptions began as functional problems rather than structural ones. However, the team observed that the axons sometimes restored transport spontaneously in an acute model of EAE. Furthermore, they were also able to reverse damage to transport therapeutically, with acute anti-inflammatory application or with redox scavenging.
But the transport issues persisted in chronic models of EAE, suggesting that sustained axonal transport deficits may also be present in humans with progressive MS. The researchers noted that anterograde transport—the central-to-distal direction of transport—was mostly diminished in the cells, ultimately starving axons of essential organelles. Therefore, detection and early treatment of transport deficits may represent an effective treatment, particularly before relapsing MS slips into the progressive stage.
Key open questions
- How can clinicians detect axonal transport deficits in humans with MS?
- What drugs may be good candidates for this sort of treatment?
Disclosures and sources of funding
This work is financed through grants from the Deutsche Forschungsgemeinschaft, the German Federal Ministry of Research and Education, the European Research Council under the European Union’s Seventh Framework Program, the Hertie Foundation, the Center for Integrated Protein Science, the German Center for Neurodegenerative Disease, the Munich Center for Systems Neurology, and DFG Priority Program 1710. D.M. holds a stipendiary professorship of the Swiss National Science Foundation (No. PP00P3_152928) and is supported by the Klaus Tschira Foundation and the Gebert Rüf Foundation.