Axonal transport

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Axonal transport, also called axoplasmic transport or axoplasmic flow, is a cellular process responsible for movement of mitochondria, lipids, synaptic vesicles, proteins, and other organelles to and from a neuron's cell body, through the cytoplasm of its axon called the axoplasm. [1] 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 lysosomes. [2]

Contents

Dynein, a motor protein responsible for retrograde axonal transport, carries vesicles and other cellular products toward the cell bodies of neurons. Its light chains bind the cargo, and its globular head regions bind the microtubule, "inching" along it. Cytoplasmic dynein.svg
Dynein, a motor protein responsible for retrograde axonal transport, carries vesicles and other cellular products toward the cell bodies of neurons. Its light chains bind the cargo, and its globular head regions bind the microtubule, "inching" along it.

Movement toward the cell body is called retrograde transport and movement toward the synapse is called anterograde transport. [3] [4]

Mechanism

Kinesin walking on a microtubule. It is a molecular biological machine that uses protein domain dynamics on nanoscales Kinesin walking.gif
Kinesin walking on a microtubule. It is a molecular biological machine that uses protein domain dynamics on nanoscales

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. [5] [6] 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). [7] 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. [8] Fluorescent labeling techniques (e.g. fluorescence microscopy) have enabled direct visualization of transport in living neurons.

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. [9] 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. [10] [11] [12] 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 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 [4] is mediated by kinesins. [2] Several kinesins have been implicated in slow transport, [8] 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 neurofilaments at 0.1-1 millimeters per day, and slow component b (SCb) that carries over 200 diverse proteins and actin at a rate of up to 6 millimeters per day. [8] 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, and uses anterograde transport mechanisms to migrate from dorsal root ganglia neurons to the skin or mucosa that it subsequently affects. [13]

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. [14] 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. [15]

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. [16] Transport from hippocampus to forebrain is decreased in aging and destination is altered by the presence of Alzheimer's disease plaques. [17]

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. [2] Operating at average in vivo speeds of approximately 2 μm/sec, [18] [19] fast retrograde transport can cover 10-20 centimeters per day. [2]

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. [20] 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. [21] Herpes simplex virus travels both ways in axons depending on its life cycle, with retrograde transport dominating polarity for incoming capsids. [22]

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. [23] [24] Dysfunctional axonal transport is also linked to sporadic (common) forms of neurodegenerative diseases such as Alzheimer's and Parkinson's. [8] 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. [25] The tetanus neurotoxin is internalised at the neuromuscular junction through binding the nidogen proteins and is retrogradely transported towards the soma in signaling endosomes. [26] Neurotropic viruses, such as the herpesviruses, travel inside axons using cellular transport machinery, as has been shown in work by Elaine Bearer's group. [27] [28] Other infectious agents are also suspected of using axonal transport. [29] Such infections are now thought to contribute to Alzheimer's disease and other neurodegenerative neurological disorders. [30] [31]

See also

Related Research Articles

<span class="mw-page-title-main">Axon</span> Long projection on a neuron that conducts signals to other neurons

An axon or nerve fiber is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action potentials away from the nerve cell body. The function of the axon is to transmit information to different neurons, muscles, and glands. In certain sensory neurons, such as those for touch and warmth, the axons are called afferent nerve fibers and the electrical impulse travels along these from the periphery to the cell body and from the cell body to the spinal cord along another branch of the same axon. Axon dysfunction can be the cause of many inherited and acquired neurological disorders that affect both the peripheral and central neurons. Nerve fibers are classed into three types – group A nerve fibers, group B nerve fibers, and group C nerve fibers. Groups A and B are myelinated, and group C are unmyelinated. These groups include both sensory fibers and motor fibers. Another classification groups only the sensory fibers as Type I, Type II, Type III, and Type IV.

<span class="mw-page-title-main">Neuroanatomy</span> Branch of neuroscience

Neuroanatomy is the study of the structure and organization of the nervous system. In contrast to animals with radial symmetry, whose nervous system consists of a distributed network of cells, animals with bilateral symmetry have segregated, defined nervous systems. Their neuroanatomy is therefore better understood. In vertebrates, the nervous system is segregated into the internal structure of the brain and spinal cord and the series of nerves that connect the CNS to the rest of the body. Breaking down and identifying specific parts of the nervous system has been crucial for figuring out how it operates. For example, much of what neuroscientists have learned comes from observing how damage or "lesions" to specific brain areas affects behavior or other neural functions.

A histochemical tracer is a compound used to reveal the location of cells and track neuronal projections. A neuronal tracer may be retrograde, anterograde, or work in both directions. A retrograde tracer is taken up in the terminal of the neuron and transported to the cell body, whereas an anterograde tracer moves away from the cell body of the neuron.

<span class="mw-page-title-main">Kinesin</span> Eukaryotic motor protein

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). The active movement of kinesins supports several cellular functions including mitosis, meiosis and transport of cellular cargo, such as in axonal transport, and intraflagellar transport. Most kinesins walk towards the plus end of a microtubule, which, in most cells, entails transporting cargo such as protein and membrane components from the center of the cell towards the periphery. This form of transport is known as anterograde transport. In contrast, dyneins are motor proteins that move toward the minus end of a microtubule in retrograde transport.

<span class="mw-page-title-main">Dynein</span> Class of enzymes

Dyneins are a family of cytoskeletal motor proteins that move along microtubules in cells. They convert the chemical energy stored in ATP to mechanical work. Dynein transports various cellular cargos, provides forces and displacements important in mitosis, and drives the beat of eukaryotic cilia and flagella. All of these functions rely on dynein's ability to move towards the minus-end of the microtubules, known as retrograde transport; thus, they are called "minus-end directed motors". In contrast, most kinesin motor proteins move toward the microtubules' plus-end, in what is called anterograde transport.

Axoplasm is the cytoplasm within the axon of a neuron. For some neuronal types this can be more than 99% of the total cytoplasm.

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 microfilaments (7 nm), they form the neuronal cytoskeleton. They are believed to function primarily to provide structural support for axons and to regulate axon diameter, which influences nerve conduction velocity. The proteins that form neurofilaments are members of the intermediate filament protein family, which is divided into six types based on their gene organization and protein structure. Types I and II are the keratins which are expressed in epithelia. Type III contains the proteins vimentin, desmin, peripherin and glial fibrillary acidic protein (GFAP). Type IV consists of the neurofilament proteins NF-L, NF-M, NF-H and α-internexin. Type V consists of the nuclear lamins, and type VI consists of the protein nestin. The type IV intermediate filament genes all share two unique introns not found in other intermediate filament gene sequences, suggesting a common evolutionary origin from one primitive type IV gene.

<span class="mw-page-title-main">Motor protein</span> Class of molecular proteins

Motor proteins are a class of molecular motors that can move along the cytoplasm of cells. They convert chemical energy into mechanical work by the hydrolysis of ATP. Flagellar rotation, however, is powered by a proton pump.

<span class="mw-page-title-main">Neurodegenerative disease</span> Central nervous system 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 lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.

<span class="mw-page-title-main">Herpes simplex virus</span> Species of virus

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<span class="mw-page-title-main">KIF5A</span> Protein-coding gene in humans

Kinesin family member 5A is a protein that in humans is encoded by the KIF5A gene. It is part of the kinesin family of motor proteins.

<span class="mw-page-title-main">Chromatolysis</span> Dissolution of a neurons Nissl bodies

In cellular neuroscience, chromatolysis is the dissolution of the Nissl bodies in the cell body of a neuron. It is an induced response of the cell usually triggered by axotomy, ischemia, toxicity to the cell, cell exhaustion, virus infections, and hibernation in lower vertebrates. Neuronal recovery through regeneration can occur after chromatolysis, but most often it is a precursor of apoptosis. The event of chromatolysis is also characterized by a prominent migration of the nucleus towards the periphery of the cell and an increase in the size of the nucleolus, nucleus, and cell body. The term "chromatolysis" was initially used in the 1940s to describe the observed form of cell death characterized by the gradual disintegration of nuclear components; a process which is now called apoptosis. Chromatolysis is still used as a term to distinguish the particular apoptotic process in the neuronal cells, where Nissl substance disintegrates.

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<span class="mw-page-title-main">Retrograde tracing</span> Technique for mapping neural circuits in the "upstream" direction, from target to source

Retrograde tracing is a research method used in neuroscience to trace neural connections from their point of termination to their source. Retrograde tracing techniques allow for detailed assessment of neuronal connections between a target population of neurons and their inputs throughout the nervous system. These techniques allow the "mapping" of connections between neurons in a particular structure and the target neurons in the brain. The opposite technique is anterograde tracing, which is used to trace neural connections from their source to their point of termination. Both the anterograde and retrograde tracing techniques are based on the visualization of axonal transport.

<span class="mw-page-title-main">KIF1A</span> Motor protein in humans

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<span class="mw-page-title-main">Neurotubule</span>

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<span class="mw-page-title-main">Campenot chamber</span>

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<span class="mw-page-title-main">Casper Hoogenraad</span> Dutch biologist

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References

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