Axonal transport

The vast majority of axonal proteins are synthesized in the neuronal cell body and transported along axons. Some mRNA translation has been demonstrated within axons. Axonal transport occurs throughout the life of a neuron and is essential to its growth and survival. Microtubules (made of tubulin) run along the length of the axon and provide the main cytoskeletal "tracks" for transportation. Kinesin and dynein are motor proteins that move cargoes in the anterograde (forwards from the soma to the axon tip) and retrograde (backwards to the soma (cell body) directions, respectively. Motor proteins bind and transport several different cargoes including mitochondria, cytoskeletal polymers, autophagosomes, and synaptic vesicles containing neurotransmitters. Axonal transport can be fast or slow, and anterograde (away from the cell body) or retrograde (conveys materials from axon to cell body). ==Fast and slow transport==

Vesicular cargoes move relatively fast (50–400 mm/day) whereas transport of soluble (cytosolic) and cytoskeletal proteins takes much longer (moving at less than 8 mm/day). The basic mechanism of fast axonal transport has been understood for decades but the mechanism of slow axonal transport is only recently becoming clear, as a result of advanced imaging techniques. The movement of soluble (cytosolic) cargoes is more complex, but appears to have a similar basis where soluble proteins organize into multiprotein complexes that are then conveyed by transient interactions with more rapidly moving cargoes moving in fast axonal transport. An analogy is the difference in transport rates between local and express subway trains. Though both types of train travel at similar velocities between stations, the local train takes much longer to reach the end of the line because it stops at every station whereas the express makes only a few stops on the way. ==Anterograde transport==

, a motor protein walking on a microtubule. Kinesin uses protein domain dynamics on nanoscales, observable by neutron spin echo spectroscopy. Anterograde (also called "orthograde") transport is movement of molecules/organelles outward, from the cell body (also called soma) to the synapse or cell membrane. The anterograde movement of individual cargoes (in transport vesicles) of both fast and slow components along the microtubule A cargo-receptor for anterograde transport motors, the kinesins, has been identified as the amyloid precursor protein (APP), the parent protein that produces the senile plaques found in Alzheimer's disease. A 15-amino acid peptide in the cytoplasmic carboxyl terminus of APP binds with high affinity to conventional kinesin-1 and mediates transport of exogenous cargo in the giant axon of the squid. Manganese, a contrast agent for T1-weighted MRI, travels by anterograde transport after stereotaxic injection into the brain of experimental animals and thereby reveals circuitry by whole brain MR imaging in living animals, as pioneered by Robia Pautler, Elaine Bearer and Russ Jacobs. Studies in kinesin-light chain-1 knockout mice revealed that Mn2+ travels by kinesin-based transport in the optic nerve and in the brain. Transport in both hippocampal projections and in the optic nerve also depends on APP. Transport from hippocampus to forebrain is decreased in aging and destination is altered by the presence of Alzheimer's disease plaques. ==Retrograde transport==

Retrograde transport shuttles molecules/organelles away from axon terminals toward the cell body. Retrograde axonal transport is mediated by cytoplasmic dynein, and is used for example to send chemical messages and endocytosis products headed to endolysosomes from the axon back to the cell. fast retrograde transport can cover 10-20 centimeters per day. Some pathogens exploit this process to invade the nervous system. They enter the distal tips on an axon and travel to the soma by retrograde transport. Examples include tetanus toxin and the herpes simplex, rabies, and polio viruses. In such infections, the delay between infection and the onset of symptoms corresponds to the time needed for the pathogens to reach the somata. Herpes simplex virus travels both ways in axons depending on its life cycle, with retrograde transport dominating polarity for incoming capsids. ==Consequences of interruption==

Whenever axonal transport is inhibited or interrupted, normal physiology becomes pathophysiology, and an accumulation of axoplasm, called an axonal spheroid, may result. Because axonal transport can be disrupted in a multitude of ways, axonal spheroids can be seen in many different classes of diseases, including genetic, traumatic, ischemic, infectious, toxic, degenerative and specific white matter diseases called leukoencephalopathies. Several rare neurodegenerative diseases are linked to genetic mutations in the motor proteins, kinesin and dynein, and in those cases, it is likely that axonal transport is a key player in mediating pathology. Dysfunctional axonal transport is also linked to sporadic (common) forms of neurodegenerative diseases such as Alzheimer's and Parkinson's. This is mainly due to numerous observations that large axonal accumulations are invariably seen in affected neurons, and that genes known to play a role in the familial forms of these diseases also have purported roles in normal axonal transport. However, there is little direct evidence for involvement of axonal transport in the latter diseases, and other mechanisms (such as direct synaptotoxicity) may be more relevant. Arrest of axoplasmic flow at the edge of ischemic areas in vascular retinopathies leads to swelling of nerve fibres, which give rise to soft exudates or cotton-wool patches. Since the axon depends on axoplasmic transport for vital proteins and materials, injury, such as diffuse axonal injury, which interrupts the transport, will cause the distal axon to degenerate in a process called Wallerian degeneration. Cancer drugs that interfere with cancerous growth by altering microtubules (which are necessary for cell division) damage nerves because the microtubules are necessary for axonal transport. ==Infection==

The rabies virus reaches the central nervous system by retrograde axoplasmic flow. The tetanus neurotoxin is internalised at the neuromuscular junction through binding the nidogen proteins and is retrogradely transported towards the soma in signaling endosomes. Neurotropic viruses, such as the herpesviruses, travel inside axons using cellular transport machinery, as has been shown in work by Elaine Bearer's group. Other infectious agents are also suspected of using axonal transport. Such infections are now thought to contribute to Alzheimer's disease and other neurodegenerative neurological disorders. ==See also==