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PubMed1998

Retrograde axonal transport of neurotrophins: differences between neuronal populations and implications for motor neuron disease.

During development, neurons die if they do not receive neurotrophin support from the target cells they are innervating. Neurotrophins are delivered from the target to the cell bodies of the innervating neurons by interacting with specific receptors located on the nerve terminals and then together are retrogradely transported to the cell body. This process consists of a number of distinct events including endocytosis of neurotrophin and its receptor into coated vesicles; vesicle sorting followed by retrograde axonal transport to the cell body, where interaction of the activated receptor initiates a signalling cascade at the cell body that causes the survival response. It has recently been shown that the signalling molecules associated with retrograde transport differ between neuronal populations. In sympathetic but not sensory neurons, a wortmannin-sensitive molecule (phosphatidylinositol kinase) is essential for the retrograde transport of neurotrophins. In sensory but not sympathetic neurons, a rapamycin-sensitive molecule (pp70S6K) is associated with retrograde transport of neurotrophins. This is strong evidence that sympathetic and sensory neurons utilize different signalling pathways to perform the same cellular function; retrograde transport. These findings may provide clues to understanding neurological diseases, such as motor neuron disease, in which axonal transport is impaired specifically in motor neurons.

Animals↗
PubMed1998

The slow axonal transport of cytoskeletal proteins.

Once presumed to be relatively uniform, the axonal cytoskeleton can vary markedly in size and composition along its length. New studies emphasize the interactiveness of neurofilaments and identify a family of cytoskeletal proteins that may cross-link the various cytoskeletal polymers of the axon, and anchor this network to the membrane skeleton. These and other findings support a model of the axonal cytoskeleton as a stationary but dynamic structure. Current evidence continues to support the possibility that axonally transported polymers/oligomers and/or monomers may serve as precursors to the cytoskeleton in different situations. Although the motors for slow transport of cytoskeletal proteins remain elusive, possible candidates are emerging.

Actin Cytoskeleton↗
PubMed1982

Blockade of retrograde axonal transport delays the onset of metabolic and morphologic changes induced by axotomy.

Axotomy-induced increase in 2-deoxyglucose (2-DG) uptake by motor nuclei and neuronal chromatolytic changes were studied after subepineural injection of colchicine into the motor nerve. Hypoglossal nuclei of either cats or rats were axotomized bilaterally, while one of the nerves was injected with colchicine or saline proximal to the site of nerve transection and the other was left intact or injected with saline. Colchicine abolished or decreased the uptake of 2-DG by axotomized nuclei and delayed the onset of chromatolysis. The decrease in 2-DG uptake was observed in rat hypoglossal nuclei between 24 and 48 hr but not 5 days after drug treatment. In turn, a delay in the onset of chromatolysis was observed in cat hypoglossal nuclei at 14 days but not 30 days after treatment. Saline did not prevent chromatolysis nor the increased uptake of 2-DG. Colchicine injected intraneurally in intact preparations did not result in chromatolysis or in increased 2-DG uptake. Following colchicine injection, the drug remained localized near the site of injection and blocked retrograde axonal transport of horseradish peroxidase in the hypoglossal nerve. These findings suggest that the onset of chromatolysis and of the increase in 2-DG uptake after axotomy are partly dependent upon retrograde axonal transport.

Afferent Pathways↗
PubMed1983

Axonal transport of noradrenaline, protein and glycoprotein in cat hypogastric nerves in vitro under conditions of high extracellular glucose.

Inferior mesenteric ganglia with attached hypogastric nerves were removed from anaesthetised cats and maintained in Eagle's Minimal Essential Medium in specially designed organ culture chambers for 48 h at 37 degrees C. The chambers had removable barriers so that the fluid bathing the ganglia was separated from that bathing the nerve trunks by inert silicone grease seals. (3H)-fucose (1.25 muCi/ml) and (14C)-leucine (0.5 muCi/ml) were added to the fluid bathing the ganglia at the start of the experiment. At this time, tight ligatures were applied to the hypogastric nerves so that the incorporated isotopes accumulated proximal to the constrictions due to interrupted axonal transport. The nerve trunks were bathed in medium containing glucose at either 5.5 or 25 mmol/l. At the end of the incubation period, the accumulations, proximal to the constrictions, of incorporated leucine and fucose and of noradrenaline were measured. The high glucose medium caused a 27.5% (p less than 0.001) reduction in the accumulation of fucose and a 19.2% (p less than 0.01) reduction in the accumulation of leucine. The incorporation of these tracers in the ganglia was unaffected by exposure of the nerve trunks to high glucose. The accumulation of noradrenaline proximal to the constrictions was also unaffected. Further experiments were performed to show that the reduced accumulations of fucose and leucine under conditions of high glucose were not due to loss of isotope from macromolecules in the axons nor to the small increase in osmotic pressure effected by addition of extra glucose to the culture medium. It is therefore suggested that elevation of extracellular glucose caused an impairment of axonal transport of incorporated leucine and fucose.

Animals↗
PubMed1990

[The role of axonal transport in regulating the chemosensitivity of muscle spindles in the cat].

The effects of acetylcholine, subecholine and succinylcholine on the afferent activity of the m.EDL muscle spindles were compared before and after suppression of axonal transport by colchicine (20 nM, 30 min). The colchicine increased cholinergic sensitivity of nuclear-bag fibres: i. a. administration of cholinergic substances at concentrations tenfold lower than in control animals, produced a sharp enhancement of afferent activity of the muscle spindles. The increase of chemosensitivity was maximal to Ach and less obvious for subecholine and succinylcholine. No increase of activity could be produced by cholinomimetics in afferents originating from nuclear-chain fibres either in control, or after suppression of axonal transport.

Acetylcholine↗
PubMed1985

Cytoarchitectural fields and retinal termination: an axonal transport study of laminar organization in the avian optic tectum.

The cytoarchitecture in the retinoreceptive zone of the pigeon optic tectum has been studied in Nissl-stained sections taken in four planes. As suggested by a previous study, two cytoarchitectural fields are present. Reconstructed views of the tectum show that the fields are separated by a narrow transition zone approximating to the tectal representation of the retina's horizontal meridian. In field 1 (which is upper and rostral), sublayer IIb is wide, IIc wide and trilaminate, IId narrow and IIe continuous; in field 2, IIb and c are narrow, IId wide and IIe discontinuous. The distribution of retinal terminals was investigated by the anterograde axonal transport of [3H]proline or horseradish peroxidase from intravitreal injections. The depth distribution of grains or reaction product throughout the entire tectum was quantified by scanning with a microdensitometer. Both autoradiography and horseradish peroxidase transport show two patterns of lamination separated by a narrow transition zone and these two terminal fields correspond closely to the cytoarchitectural fields. In field 1 optic terminals are concentrated in sublayer IIb, superficial c, d, and to a lesser extent in f; in field 2 concentrations are present at the IIb/c boundary, across deep IIc and d, and a small concentration is found IIf. The patterns of retinal termination with depth in the tectum found by axonal transport are compatible with those found by electron microscopy, and are discussed in relation to the optic termination found by other techniques. Study of the time course of axonal transport shows that both radioactive material and horseradish peroxidase are fast transported to all the bands of optic terminals at about 150 mm/day. Horseradish peroxidase gradually accumulates in the retinoreceptive zone, filling clusters of terminals and horizontal processes. At 12 days, it has begun to disappear from the zone and a few diffusely filled profiles, that may be transcellularly labelled, are present. Electron microscope autoradiography of fast transported material shows clusters of grains over optic terminals and preterminals and a percentage density analysis confirms that these profiles are specifically labelled. The two tectal fields each contain the projection from specialized areas of the retina, suggesting functional specialization in the tectum for the processing of different kinds of visual information.

Animals↗
PubMed1981

Axonal transport of calmodulin: a physiologic approach to identification of long-term associations between proteins.

Calmodulin is a soluble, heat-stable protein which has been shown to modulate both membrane-bound and soluble enzymes, but relatively little has been known about the in vivo associations of calmodulin. A 17,000-dalton heat-stable protein was found to move in axonal transport in the guinea pig visual system with the proteins of slow component b (SCb; 2 mm/d) along with actin and the bulk of the soluble proteins of the axon. Co-electrophoresis of purified calmodulin and radioactively labeled SCb proteins in two dimensional polyacrylamide gel electrophoresis (PAGE) demonstrated the identity of the heat-stable SCb protein and calmodulin on the basis of pI, molecular weight, and anomalous migration in the presence of Ca2+-chelating agents. No proteins co-migrating with calmodulin in two-dimensional PAGE could be detected among the proteins of slow component a (SCa; 0.3 mm/d, microtubules and neurofilaments) or fast component (FC; 250 mm/d, membrane-associated proteins). We conclude that calmodulin is transported solely as part of the SCb complex of proteins, the axoplasmic matrix. Calmodulin moves in axonal transport independent of the movements of microtubules (SCa) and membranes (FC), which suggests that the interactions of calmodulin with these structures may represent a transient interaction between groups of proteins moving in axonal transport at different rates. Axonal transport has been shown to be an effective tool for the demonstration of long-term in vivo protein associations.

Actins↗
PubMed2000

Signalling organelle for retrograde axonal transport of internalized neurotrophins from the nerve terminal.

The retrograde axonal transport of neurotrophins occurs after receptor-mediated endocytosis into vesicles at the nerve terminal. We have been investigating the process of targeting these vesicles for retrograde transport, by examining the transport of [125I]-labelled neurotrophins from the eye to sympathetic and sensory ganglia. With the aid of confocal microscopy, we examined the phenomena further in cultures of dissociated sympathetic ganglia to which rhodamine-labelled nerve growth factor (NGF) was added. We found the label in large vesicles in the growth cone and axons. Light microscopic examination of the sympathetic nerve trunk in vivo also showed the retrogradely transported material to be sporadically located in large structures in the axons. Ultrastructural examination of the sympathetic nerve trunk after the transport of NGF bound to gold particles showed the label to be concentrated in relatively few large organelles that consisted of accumulations of multivesicular bodies. These results suggest that in vivo NGF is transported in specialized organelles that require assembly in the nerve terminal.

Animals↗
PubMed1994

Release of slow axonally transported proteins from the rat vagus nerve in vitro.

The cultured rat vagus nerve was used to investigate the release of [35S]methionine-labelled slow axonally transported proteins during regeneration. After metabolic labelling the released proteins were collected from an isolated compartment at the distal end of the nerve. Several proteins were released at a time point consistent with the arrival of slow axonally transported proteins at the collection compartment, including actin and a group of 150 kDa proteins.

Animals↗
PubMed1986

Rapid axonal transport of the neural cell adhesion molecule.

The neural cell adhesion molecule (NCAM) is a cell-surface glycoprotein that mediates cell-cell interactions in the nervous system during development. In the present study, we demonstrate that NCAM is axonally transported in 3-d-old chick retinal ganglion cells and that it travels within the fast component of axonal transport (FC). Proteins were radiolabeled in retinal ganglion cell bodies after intraocular injection of 35S-methionine. The presence of radiolabeled NCAM in the optic nerves and contralateral tecta was detected by specific immunoadsorption to a monoclonal antibody. Major radioactive polypeptide bands at relative mobilities of approximately 200,000, 150,000, and 120,000 Mr (after SDS-PAGE) were recognized by the anti-NCAM antibody. These bands comigrated in 1-dimensional gels with components of purified NCAM from chick brain. The 2 largest NCAM polypeptides (at 200,000 and 150,000 Mr) were found to be transported in this system, while the 120,000 Mr form was apparently not transported. The ratio and electrophoretic profiles of the 2 transported forms of NCAM remained similar in the retina, optic nerve, chiasm, tract, and tectum, suggesting that there is no interconversion of the 2 major polypeptides. The fraction of NCAM in the 35S-labeled FC proteins appears to be at least an order of magnitude less than in the plasma membrane, suggesting that the turnover rate of NCAM at this age is slower than for other membrane proteins of the CNS.

Animals↗
PubMed1985

Axonal transport of a heat shock protein in the rabbit visual system.

Intraocular injection of [35S]methionine was used to demonstrate the pronounced induction of a 74-kDa heat shock protein in the rabbit retina after a 3 degrees C increase in body temperature was generated by intravenous administration of D-lysergic acid diethylamide. Two-dimensional polyacrylamide gel electrophoresis and fluorography revealed that the induced heat shock protein underwent axonal transport from retinal ganglion cells into the optic nerve and subsequently down the contralateral optic tract to synaptic termini in the visual projection area. Since the heat shock protein took more than 8 days to move down the optic nerve to the superior colliculus, it is transported by slow rather than by fast axonal transport.

Animals↗
PubMed1989

Heat stress increases delivery of a unique sub-population of proteins conveyed by fast axonal transport.

The effect of heat stress on protein synthesis and fast axonal transport was examined in vitro in bullfrog dorsal root ganglion (DRG) and associated spinal/sciatic nerve. Qualitative and quantitative changes of individual 35S-methionine-labelled proteins were determined following DRG labelling and fast transport in respective nerves via two-dimensional gel electrophoresis/autoradiography. Elevation of temperature from 18 degrees C to 33 degrees C for up to 6 hr resulted in a marked increase in synthesis of five individual DRG species of approximately 74,000 daltons that comigrate with heat shock proteins (HSPs). A quantitative comparison of species within this subset revealed two subgroups differentially affected by stress. The three most basic proteins were induced to approximately 1300% of unstressed controls after 6 hr of stress, while the two most acidic species demonstrated an increase to only 300% of controls over the same period. The relative abundance of 25 additional DRG proteins were uneffected by heat stress. Of 70 35S-labelled fast-transported proteins similarly analyzed, 15, comprising 5 families, were consistently transported at greater than 150% of controls following up to 6 hr of heat stress. Over this period all 15 proteins shared a similar profile of abundance relative to non-induced proteins. Transport was elevated to the greatest extent after 2 hr of stress, declined after 3 hr, and tended to rebound at later times. The remaining 55 fast-transported protein spots analyzed were unaffected. An increased delivery of this unique sub-population of 15 fast-transported proteins suggests a possible involvement in early cellular events that mediate heat stress in the nervous system.

Animals↗
PubMed2004

Enhanced detection and retrograde axonal transport of PrPc in peripheral nerve.

Neuroinvasion of the CNS during orally acquired transmissible spongiform encephalopathies (TSEs) may involve the transport of the infectious agent from the periphery to the CNS via the peripheral nerves. If this occurs within axons, the mechanism of axonal transport may be fundamental to the process. In studies of peripheral nerve we observed that the cellular prion protein (PrPc) is highly resistant to detergent extraction. The implication of this is an underestimation of the abundance of PrPc in peripheral nerve. We have developed nerve extraction conditions that enhance the quantification of the protein in nerve 16-fold. Application of these conditions to evaluate the accumulation of PrPc distal to a cut nerve now reveals that PrPc is retrogradely transported from the axon ending. These results provide a potential cellular mechanism for TSE infectivity to gain entry to the CNS from the periphery.

Animals↗
PubMed1989

Toxic neurofilamentous axonopathies and fast anterograde axonal transport. II. The effects of single doses of neurotoxic and non-neurotoxic diketones and beta, beta'-iminodipropionitrile (IDPN) on the rate and capacity of transport.

The site and mode of action of neurotoxic chemicals producing neurofilamentous axonopathies has been speculated to be the axonal transport system. The current study determined the effects of neurotoxic and non-neurotoxic gamma-diketones as well as beta, beta'-iminodipropionitrile (IDPN) upon both the rate and quantity of protein transported in the fast anterograde component of the rat sciatic nerve. 2,5-Hexanedione (2,5-HD), given as 4, 6 and 8 mmoles/kg single ip injections reduced the rate of transport by 18.4-24.7% but more significantly reduced the quantity of protein transported 50-63%. 3,4-Dimethyl-2,5-HD (3,4-DMHD) at single doses of 0.25, 0.50 and 1.0 mmoles/kg similarly reduced the rate and capacity of protein transport. The toxicants did not alter the uptake of leucine and synthesis of protein during the three hour time frame used to measure transport. Although high doses of IDPN reduced the rate of anterograde transport, this toxicant, as well as the non-neurotoxic diketones studied, had no effect upon the quantity of protein transported. Therefore, neurotoxic gamma-diketones which produce distal nerve degeneration had a common effect in decreasing the quantity of protein delivered to the nerve after just a single exposure.

Animals↗
PubMed1992

Axonal transport of class II and III beta-tubulin: evidence that the slow component wave represents the movement of only a small fraction of the tubulin in mature motor axons.

Pulse-labeling studies demonstrate that tubulin synthesized in the neuron cell body (soma) moves somatofugally within the axon (at a rate of several millimeters per day) as a well-defined wave corresponding to the slow component of axonal transport. A major goal of the present study was to determine what proportion of the tubulin in mature motor axons is transported in this wave. Lumbar motor neurons in 9-wk-old rats were labeled by injecting [35S]methionine into the spinal cord 2 wk after motor axons were injured (axotomized) by crushing the sciatic nerve. Immunoprecipitation with mAbs which recognize either class II or III beta-tubulin were used to analyze the distributions of radioactivity in these isotypes in intact and axotomized motor fibers 5 d after labeling. We found that both isotypes were associated with the slow component wave, and that the leading edge of this wave was enriched in the class III isotype. Axotomy resulted in significant increases in the labeling and transport rates of both isotypes. Immunohistochemical examination of peripheral nerve fibers demonstrated that nearly all of the class II and III beta-tubulin in nerve fibers is located within axons. Although the amounts of radioactivity per millimeter of nerve in class II and III beta-tubulin were significantly greater in axotomized than in control nerves (with increases of +160% and +58%, respectively), immunoassay revealed no differences in the amounts of these isotypes in axotomized and control motor fibers. We consider several explanations for this paradox; these include the possibility that the total tubulin content is relatively insensitive to changes in the amount of tubulin transported in the slow component wave because this wave represents the movement of only a small fraction of the tubulin in these motor fibers.

Amino Acid Sequence↗
PubMed1985

Changes in axonal transport of phospholipids in the regenerating goldfish optic system.

Changes in axonally transported phospholipids of regenerating goldfish optic nerve were studied by intraocular injection of [2-3H]glycerol 9 days and 16 days after nerve crush at 30 degrees C. The four major glycerophospholipids all showed substantial increases in transported radioactivity above non-regenerating controls at both time points, these being maximal (15- to 35-fold) in the optic nerve-tract at 9 days and about half as great at 16 days. In the contralateral optic tectum transported label increased 6- to 13-fold at 9 days and 10- to 25-fold at 16 days in the various glycerophospholipids. While all glycerophospholipids showed absolute increases in both tissues, PS and PI increased relatively more, especially in the tectum. The regeneration-associated increases in transported label of all glycerophospholipids were larger than those previously demonstrated for gangliosides and glycoproteins in the same system.

Animals↗
PubMed1995

Interleukin-1 beta induces long-term increase of axonally transported opiate receptors and substance P.

Interleukin-1 is known to exert pleiotropic effects in host defence mechanisms and in inflammation. Chronic pain, inflammation and interleukin-1 beta enhance the production of substance P. Recently, axonal transport of opiate receptors was found to increase in rat sciatic nerves in the model of Freund's adjuvant-induced arthritis. Here we show that a single intraplantar injection of interleukin-1 beta is able to enhance the axonal transport of mu and kappa opiate receptors and substance P. Indeed, their accumulation was markedly increased in the proximal part of ligated sciatic nerves, but only in the paw injected with interleukin-1. The time course revealed a delayed onset and, more importantly, a long-term increase lasting at least six days, which is in contrast with the short-term pyrogenic effect of interleukin-1. Pretreatment of rats with capsaicin or administration of dexamethasone completely prevented the interleukin-1 beta effect. The present results suggest that interleukin-1 beta may serve as a mediator to sensitize nociceptors in chronic inflammation and possibly in hyperalgesia through long-term changes in neuronal plasticity.

Animals↗