Axonal transport, also called axoplasmic transport or axoplasmic flow, is a

cellular process The cell is the basic structural and functional unit of life forms. Every cell consists of a cytoplasm enclosed within a membrane, and contains many biomolecules such as proteins, DNA and RNA, as well as many small molecules of nutrients an ...

responsible for movement of mitochondria,

lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids includ ...

synaptic vesicle In a neuron, synaptic vesicles (or neurotransmitter vesicles) store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulse ...

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

s, and other organelles to and from a

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...

's cell body, through the

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...

of its

axon An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action p ...

called the

axoplasm Axoplasm is the cytoplasm within the axon of a neuron (nerve cell). For some neuronal types this can be more than 99% of the total cytoplasm. Axoplasm has a different composition of organelles and other materials than that found in the neuron's c ...

. Since some axons are on the order of meters long, neurons cannot rely on diffusion to carry products of the nucleus and organelles to the end of their axons. Axonal transport is also responsible for moving molecules destined for degradation from the axon back to the cell body, where they are broken down by

lysosome A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane pr ...

Movement toward the cell body is called retrograde transport and movement toward the synapse is called anterograde transport.

Mechanism

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.Si K, Giustetto Axonal transport occurs throughout the life of a neuron and is essential to its growth and survival. Microtubules (made of

tubulin Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or one of the member proteins of that superfamily. α- and β-tubulins polymerize into microtubules, a major component of the eukaryotic cytoske ...

) run along the length of the axon and provide the main cytoskeletal "tracks" for transportation.

Kinesin A kinesin is a protein belonging to a class of motor proteins found in eukaryotic cells. Kinesins move along microtubule (MT) filaments and are powered by the hydrolysis of adenosine triphosphate (ATP) (thus kinesins are ATPases, a type of enzy ...

and dynein are motor proteins that move cargoes in the anterograde (forwards from the

soma Soma may refer to: Businesses and brands * SOMA (architects), a New York–based firm of architects * Soma (company), a company that designs eco-friendly water filtration systems * SOMA Fabrications, a builder of bicycle frames and other bicycle ...

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 The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compo ...

polymer A polymer (; Greek '' poly-'', "many" + ''-mer'', "part") is a substance or material consisting of very large molecules called macromolecules, composed of many repeating subunits. Due to their broad spectrum of properties, both synthetic a ...

s, autophagosomes, and

s 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. Fluorescent labeling techniques (e.g.

fluorescence microscopy A fluorescence microscope is an optical microscope that uses fluorescence instead of, or in addition to, scattering, reflection, and attenuation or absorption, to study the properties of organic or inorganic substances. "Fluorescence microscop ...

) have enabled direct visualization of transport in living neurons. (See also: Anterograde tracing.) Recent studies have revealed that the movement of cytoskeletal "slow" cargoes is actually rapid but unlike fast cargoes, they pause frequently, making the overall transit rate much slower. The mechanism is known as the "Stop and Go" model of slow axonal transport, and has been extensively validated for the transport of the cytoskeletal protein neurofilament. The movement of soluble (cytosolic) cargoes is more complex, but appears to have a similar basis where soluble proteins organize into multi-protein 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

Anterograde (also called "orthograde") transport is movement of molecules/organelles outward, from the cell body (also called

) to the synapse or

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...

. The anterograde movement of individual cargoes (in transport vesicles) of both fast and slow components along the microtubule is mediated by

kinesin A kinesin is a protein belonging to a class of motor proteins found in eukaryotic cells. Kinesins move along microtubule (MT) filaments and are powered by the hydrolysis of adenosine triphosphate (ATP) (thus kinesins are ATPases, a type of enzy ...

s. Several kinesins have been implicated in slow transport, though the mechanism for generating the "pauses" in the transit of slow component cargoes is still unknown. There are two classes of slow anterograde transport: slow component a (SCa) that carries mainly microtubules and

neurofilament Neurofilaments (NF) are classed as type IV intermediate filaments found in the cytoplasm of neurons. They are protein polymers measuring 10 nm in diameter and many micrometers in length. Together with microtubules (~25 nm) and mi ...

s at 0.1-1 millimeters per day, and slow component b (SCb) that carries over 200 diverse proteins and

actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...

at a rate of up to 6 millimeters per day. The slow component b, which also carries actin, are transported at a rate of 2-3 millimeters per day in retinal cell axons. During reactivation from latency, the herpes simplex virus (HSV) enters its

lytic cycle The lytic cycle ( ) is one of the two cycles of viral reproduction (referring to bacterial viruses or bacteriophages), the other being the lysogenic cycle. The lytic cycle results in the destruction of the infected cell and its membrane. Bacteri ...

, and uses anterograde transport mechanisms to migrate from

dorsal root ganglia A dorsal root ganglion (or spinal ganglion; also known as a posterior root ganglion) is a cluster of neurons (a ganglion) in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the dorsal ...

neurons to the skin or mucosa that it subsequently affects. A cargo-receptor for anterograde transport motors, the kinesins, has been identified as the

amyloid precursor protein Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse format ...

(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 termini 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. Operating at average ''in vivo'' speeds of approximately 2 μm/sec, fast retrograde transport can cover 10-20 centimeters per day. Fast retrograde transport returns used synaptic vesicles and other materials to the soma and informs the soma of conditions at the axon terminals. Retrograde transport carries survival signals from the synapse back to the cell body, such as the TRK, the nerve growth factor receptor. 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 disease A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...

s are linked to

genetic mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

s in the motor proteins,

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 Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

. 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 Diffuse axonal injury (DAI) is a brain injury in which scattered lesions occur over a widespread area in white matter tracts as well as grey matter. DAI is one of the most common and devastating types of traumatic brain injury and is a major cause ...

, which interrupts the transport, will cause the distal axon to degenerate in a process called

Wallerian degeneration Wallerian degeneration is an active process of degeneration that results when a nerve fiber is cut or crushed and the part of the axon distal to the injury (i.e. farther from the neuron's cell body) degenerates. A related process of dying back o ...

. Cancer drugs that interfere with cancerous growth by altering microtubules (which are necessary for

cell division Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there ar ...

) damage nerves because the microtubules are necessary for axonal transport.

Infection

The

rabies virus Rabies virus, scientific name ''Rabies lyssavirus'', is a neurotropic virus that causes rabies in humans and animals. Rabies transmission can occur through the saliva of animals and less commonly through contact with human saliva. ''Rabies lys ...

reaches the central nervous system by retrograde axoplasmic flow. The tetanus neurotoxin is internalised at the neuromuscular junction through binding the

nidogen Nidogens, formerly known as entactins, are a family of sulfated monomeric glycoproteins located in the basal lamina of parahoxozoans. Two nidogens have been identified in humans: nidogen-1 (NID1) and nidogen-2 (NID2). Remarkably, vertebrates are ...

proteins and is retrogradely transported towards the soma in signaling endosomes. Neurotropic viruses, such 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.{{Cite journal, date=2010, title=No place like asphalt for these hardy microbes , journal=New Scientist , volume=206 , issue=2757 , pages=15 , doi=10.1016/s0262-4079(10)60991-8

References

Neurophysiology