Biology Reference
In-Depth Information
What happens when axonal transport fails? After axon injury, the ultimate
block of axonal transport, total and permanent isolation of a distal axon from its cell
body results inWallerian degeneration of the distal stump 1-2 days later. Wallerian
degeneration involves a poorly understood latent phase, followed by characteristic
granular disintegration of the axonal cytoskeleton, glial reaction, and loss of axon
continuity. It can be delayed tenfold by the slow Wallerian degeneration protein
(Wld
S
) or by relatedproteins when they are expressedor overexpressed in transgenic
animals (Coleman and Freeman, 2010). Wld
S
also delays axon degeneration in
some neurodegenerative disorders. Several of these involve disruption of axonal
transport, strongly suggesting that the trigger for Wallerian degeneration is the
failure to deliver an essential cargo (Coleman and Freeman, 2010). An alternative
model, involving an injury signal generated by the lesion, cannot explain how
Wallerian-like mechanisms can be triggered without physical injury.
Physical trauma or axon compression causes a similar, nonspecific block
of axonal transport in several human disorders. High intraocular pressure disrupts
the flow of materials at one end of the optic nerve (Howell
et al.
, 2007; Martin
, 2006), resulting in axon degeneration that Wld
S
can delay (Beirowski
et al.
et al.
, 2007). In some models of Alzheimer's disease patho-
genesis, amyloid plaques physically compress nearby structures, including axons
(Vickers
, 2008; Howell
et al.
, 2000). Spinal contusion injuries place chronic physical pressure
on underlying axons, among other effects. Traumatic brain injury stretches
axons, disrupting their cytoskeleton and axonal transport (Stone
et al.
, 2004).
Solid tumors, carpal tunnel syndrome, and other pressure palsies similarly restrict
axonal transport due to physical pressure.
However, nonspecific impairment of axonal transport does not only result
from mechanical disruption. Disruption of the microtubule “rails” along which
long-range transport runs is the most obvious way to affect all cargoes. In progres-
sive motor neuronopathy mice (
et al.
), for example, a loss-of-function mutation in
the tubulin-specific chaperone e gene leads to a severe deficiency of microtubules
in distal axons (Martin
pmn
et al.
, 2002; Schaefer
et al.
,2007). Spastin, the protein
mutated in the hereditary spastic paraplegia
SPG4
, also has critical roles in
microtubule assembly and/or severing (Evans
,2009).
Neurotoxic drugs such as Taxol and Vincristine probably alter axonal transport by
directly targeting microtubules (Shemesh and Spira, 2009; Silva
et al.
, 2005; Riano
et al.
,2006).
Thus, little or nothing can be delivered without microtubules, their building
blocks, or the chaperones that help put them together.
et al.
B. Traffic restrictions: Specific axonal transport defects
Disruption of axonal transport can be more specific in a number of ways. Ever
since the discovery of fast anterograde transport (Weiss and Hiscoe, 1948), the
complexity of axonal transport, as we understand it, has been increasing. First,
