4. List some pathogens that are transported in the retrograde direction.

I. Axonal Transport

A. Definition and Significance

1. Mitochondria, synaptic vesicles and other cytoplasmic constituents travel to and from the cell body by a process called axonal transport (also called axoplasmic transport or flow). Movements of materials away from the cell body (in the same direction as signal propagation) is called anterograde transport, while movement of materials toward the cell body is called retrograde transport.

2. To understand the significance of axonal transport, it is important to realize that the axon contains 100 times the volume of the cell body (even though it is very thin, its length may be 1,000 or 10,000 times the diameter of the cell body) but no protein synthesis takes place in the axon. Only the cell body and proximal dendrites contain ribosomes, the protein manufacturing organelles. Therefore, proteins for neuro-transmitters and membrane repair, as well as some lipids are constantly transported anterogradely from the cell body down the length of the axon to maintain normal axonal function. If the axon is deprived of proteins because it is severed or crushed, the segment that is distal to the injury cannot support itself and will degenerate.

B. Factors Influencing Transport

1. Structure: The mechanism of axonal transport is not well understood but it is known that the cellular organelles called neurotubules or microtubules, play an important role. Drugs which disrupt microtubule organization are prescribed to stop some types of cancerous cells from multiplying because the spindles on which chromosomes migrate during mitosis are microtubules. However, by disrupting the microtubules, these drugs also produce serious neurological side effects by disrupting normal neurotubule organization and interrupting axonal transport. Examples of these drugs are vinblastine and vincristine.

2. Axonal transport requires energy generated by oxidative phosphorylation (involves many mitochondria). However, transport mechanisms are independent of the electrical activity in the axon. Neither increasing nor decreasing the number of nerve impulses conducted (due to electrical stimulation) has been shown to measurably effect the rate of transport.

C. Anterograde Transport

Proteins are transported in the anterograde direction at different speeds. 1. The rapid transport component moves at a rate of 410mm/day (1.7cm/hr.) in the sciatic nerve. The speed of rapid transport may be slower in other nerves, but it is never less than lOOmm/day. Rapid transport carries mainly membrane bound materials such as plasma membrane proteins and synaptic vesicles.

2. In contrast, slow transport in the anterograde direction moves at a rate of only 1-3mm/day. Slow transport carries soluble enzymes and structural proteins such as the microtubule protein, tubulin. Unfortunately, it is the slow transport rate which determines the rate of recovery following injury to a peripheral nerve (see below).

D. Retrograde Transport

1. The rate of retrograde transport is about half that of anterograde transport. The function of retrograde transport is not well understood but it is thought that it is important in regulating metabolism of the cell. For example, when an axon is cut, the signal which induces the cell body to undergo chromatolysis is probably carried by retrograde transport.

2. Also, some neurotropic viruses such as poliomyelitis, herpes, and rabies and neurotoxins enter peripheral nerve endings and ascend to infect the cell body via retrograde transport.

E. Mechanism

1. Microtubules polymerize from tubulin subunits in a polarized fashion. The plus ends face toward the axon terminal, while the minus ends are directed toward the cell body.

2. Anterograde transport appears to require kinesin, an ATPase protein complex. Presumably, kinesin bridges between the microtubule and the transported molecule and, in the presence of ATP, undergoes conformational changes that "walk" the transported molecule towards the plus end of the microtubule.

3. A second protein complex dynein is thought to work similarly, but in the opposite direction, for retrograde transport.

II. Neuronal Response To Injury

A. Wallerian (Anterograde) Degeneration (Figures 1 & 2)

1. When an axon is cut or crushed, the axonal segments distal to the lesion begin to degenerate within one day. The myelin sheaths surrounding the distal parts of the axons also begin to break down and become detached from the oligodendroglia (CNS) or the Schwann cells (PNS). This process of degeneration occurs in the direction of nerve impulse conduction; i.e., in the anterograde direction.

2. In the peripheral nervous system, Schwann cells and macrophages remove the degenerating debris by phagocytosis over a period of one or two months. Empty endoneurial tubes lined with longitudinally oriented Schwann cells remain. These cells increase in number by cell division.

3. The process of Wallerian degeneration is similar in the CNS except that glial cells phagocytose the degenerating debris and form a (glial) scar tissue rather than the tubes formed in the PNS.

Fig. 1. Neuronal response to injury in the CNS

B. Retrograde Reaction (Figures 1 & 2)

1. In response to the injury, the cell body alters its metabolism to produce the materials needed to regenerate a new axon. The parallel arrays of rough endoplasmic reticulum known as Nissl bodies become dispersed into smaller ribosomal groupings. This dispersal of the chromatophilic Nissl substance is called chromatolysis.

C. Retrograde Degeneration (Figures 1 & 2)

1. CNS neurons are unable to successfully regenerate axons following injury. If the sole or major axonal branches of CNS neurons are destroyed, the neurons will eventually die. However, if the neuron has axon collaterals outside the injured area, these may sustain that neuron. The area containing the dying cell bodies will become infiltrated with glial cells which phagocytose degenerating neurons. This gradual formation of a glial scar is known as gliosis.

Figure 2. Neuronal response to injury and recovery in the PNS

D. Glial Scarring and Regulating Factors of Regenerating Axons (Figure 1)

1. Glial scarring is thought to present an impenetrable barrier to regenerating axons in the CNS. Also, recent studies have revealed that both astrocytes and oligodendrocytes release inhibiting factors which prevent invasion of growth cones of regenerating axons into mature CNS areas.

2. Schwann cells of the PNS do not produce these inhibiting factors but produce growth stimulating factors instead. Therefore, there is currently much interest in the transplantation of Schwann cells into CNS injury sites for promotion of axon regeneration.

E. Transneuronal Degeneration

1. In certain neural systems in the CNS, such as the visual system, injury to neurons in one portion of the pathway will eventually result in anterograde or retrograde degeneration of neurons in distant parts of the pathway.

III. Axonal Regeneration In The Peripheral Nervous System

A. Growth Cone (Figure 2)

1. Several days after the injury to a peripheral nerve, the proximal axon stump begins to send out very thin axonal sprouts. The tip of these axons is a specialized, amoeba-like region filled with microtubules called a growth cone. Growth cones act as "feelers" for the intact endoneurial tubes. A growth cone will advance down the empty endoneurial tube at a rate of 1-4mm/day, about the same rate as slow axonal transport. Thus, regeneration after a nerve injury at the elbow may take several months to restore hand function. (1 inch = 2.4 cm; 24 days @ 1mm/day & 6 days @ 4mm/day)

B. Neuromas (Figure 2)

1. Scar (connective) tissue may block the advance of growth cones and will result in a jumbled mass of trapped and regenerating axons called a neuroma. Pressure or tactile stimulation of neuromas can be unpleasant or exquisitely painful.

C. Surgical Repair

1. Successful regeneration of a severed nerve across a large open gap is highly unlikely. The chances for successful regeneration are improved if the two stumps of the nerve are anastomosed surgically. This corrective operation is usually performed several weeks after the original trauma. The surgeon cuts off any neuroma, attempts to realign the two stumps, and sutures them together using the epineurium surrounding the nerves. If the stumps are still separated by a gap, it may be bridged by nerve grafts from elsewhere in the body (usually the sural nerve).

D. Recovery

1. Even a successful operation may not allow complete restitution of function. This is because many axons grow down the wrong endoneurial paths and terminate in inappropriate regions. Regenerating adult mammalian nerves do not exhibit much specificity for their previous target organ. For instance, motor axons do not seem to be able to recognize a specific muscle to which they were once connected, but will synapse on any denervated muscle they encounter. Thus, guidance of axons to their targets by their endoneurial tubes is extremely important for good functional recovery.

2. Full recovery also requires maturation of the regenerating axons. Initially, regenerated axons are thin and unmyelinated and, as a result, their conduction velocity is slow. With time, the axons increase in diameter, become remyelinated by the adjacent Schwann cells and their physiological responses return to near normal.

V. Summary