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PubMed1995

The neuron-specific kinesin superfamily protein KIF1A is a unique monomeric motor for anterograde axonal transport of synaptic vesicle precursors.

Axonal transport has been intensively examined as a good model for studying the mechanism of organelle transport in cells, but it is still unclear how different types of membrane organelles are transported through the nerve axon. To elucidate the function of this mechanism, we have cloned KIF1A, a novel neuron-specific kinesin superfamily motor that was discovered to be a monomeric, globular molecule and that had the fastest reported anterograde motor activity (1.2 microns/s). To identify its cargo, membranous organelles were isolated from the axon. KIF1A was associated with organelles that contained synaptic vesicle proteins such as synaptotagmin, synaptophysin, and Rab3A. However, this organelle did not contain SV2, another synaptic vesicle protein, nor did it contain presynaptic membrane proteins, such as syntaxin 1A or SNAP-25, or other known anterograde motor proteins, such as kinesin and KIF3. Thus, we suggest that the membrane proteins are sorted into different classes of transport organelles in the cell body and are transported by their specific motor proteins through the axon.

Amino Acid Sequence↗
PubMed2003

Glutamate and amyloid beta-protein rapidly inhibit fast axonal transport in cultured rat hippocampal neurons by different mechanisms.

Impairment of axonal transport leads to neurodegeneration and synapse loss. Glutamate and amyloid beta-protein (Abeta) have critical roles in the pathogenesis of Alzheimer's disease (AD). Here we show that both agents rapidly inhibit fast axonal transport in cultured rat hippocampal neurons. The effect of glutamate (100 microm), but not of Abeta25-35 (20 microm), was reversible, was mimicked by NMDA or AMPA, and was blocked by NMDA and AMPA antagonists and by removal of extracellular Ca2+. The effect of Abeta25-35 was progressive and irreversible, was prevented by the actin-depolymerizing agent latrunculin B, and was mimicked by the actin-polymerizing agent jasplakinolide. Abeta25-35 induced intracellular actin aggregation, which was prevented by latrunculin B. Abeta31-35 but not Abeta15-20 exerted effects similar to those of Abeta25-35. Full-length Abeta1-42 incubated for 7 d, which specifically contained 30-100 kDa molecular weight assemblies, also caused an inhibition of axonal transport associated with intracellular actin aggregation, whereas freshly dissolved Abeta1-40, incubated Abeta1-40, and fresh Abeta1-42 had no effect. These results suggest that glutamate inhibits axonal transport via activation of NMDA and AMPA receptors and Ca2+ influx, whereas Abeta exerts its inhibitory effect via actin polymerization and aggregation. The ability of Abeta to inhibit axonal transport seems to require active amino acid residues, which is probably present in the 31-35 sequence. Full-length Abeta may be effective when it represents a structure in which these active residues can access the cell membrane. Our results may provide insight into the early pathogenetic mechanisms of AD.

Actins↗
PubMed1987

Synaptic vesicles in electromotoneurones. I. Axonal transport, site of transmitter uptake and processing of a core proteoglycan during maturation.

We were able by using an in vivo pulse-label technique to trace part of the life cycle of a secretory organelle, the acetylcholine-storing synaptic vesicle from electromotoneurones of Torpedo marmorata. This technique uses [35S]sulphate incorporation into the cell bodies of the electromotoneurones which results in radioactive labelling of a synaptic vesicle heparansulphate proteoglycan--a major core component. Vesicles are anterogradely transported in the axons at a fast rate as 'empty' organelles (VP0 population). In the nerve terminal, maturation of the granule to a population (VP1) fully charged with acetylcholine and ATP occurs. Finally after a longer time interval a change to a third population (VP2) is observed. This population is reduced in diameter as compared to VP0 and VP1 suggesting, in agreement with earlier reports, that it has undergone exo-endocytosis. The changes from VP0 to VP1 and VP2 are accompanied by a degradation of the core proteoglycan as measured by gel filtration of the 35S-labelled compound. The results show that vesicles are axonally transported as preformed organelles, exist in the neurone at least in three different populations and that the nerve terminal is the major site of transmitter uptake.

Acetylcholine↗
PubMedDate not supplied

Acrylamide-induced alterations in axonal transport. Biochemical and autoradiographic studies.

Alterations in the axonal transport of proteins, glycoproteins, and gangliosides in sensory neurons of the sciatic nerve were examined in adult male rats exposed to acrylamide (40 mg ip/kg body wt/d for nine consecutive days). Twenty-four hours after the last dose, the L5 dorsal root ganglion (DRG) was injected with either [35S]methionine to label proteins or [3H]glucosamine to label glycoproteins and gangliosides. The downflow patterns of radioactivity for [35S]methionine-labeled proteins and [3H]glucosamine-labeled gangliosides were unaltered by acrylamide treatment. In contrast, the outflow pattern of labeled glycoproteins displayed a severely attenuated crest with no alteration in velocity, suggesting a preferential transfer with the unlabeled stationary components in the axolemma. Retrograde accumulation of transported glycoproteins and gangliosides was unaltered for at least 6 h; however, by 24 h, there was a 75% decrease in the amount of accumulated material. The accumulation of [35S]methionine-labeled proteins was not altered. Autoradiographic analysis revealed an acrylamide-induced paucity of transported radiolabeled glycoproteins selectively in myelinated axons with no effect on "nonmyelinated" axons. The pattern of transported proteins was similar in both control and acrylamide-exposed animals. These results suggest a preferential inhibition of glycosylation or axonal transport of glycoproteins in neurons bearing myelinated axons. More importantly, it suggests that interpretations of axonal transport data must be made with the consideration of alterations in selective nerve fibers and not with the tacit assumption that all fibers in the nerve population are equally affected.

Acrylamide↗
PubMed1986

Effects of hypothermia on the in vivo measurement of rapid axonal transport in the rat: a cautionary note.

Rapid axonal transport of glycoproteins was examined in the retinofugal projections of hypothermic and normothermic adult male Long-Evans hooded rats previously receiving intraocular injections of [3H]fucose. The amount of retinal fucosylation appeared normal in the hypothermic animals 3.5 h after isotope injection, but glycoprotein transport was reduced relative to normothermic controls. This reduction was especially pronounced in the most distal structure of the retinofugal tract (superior colliculus). We conclude that rapid axonal transport decreases with reductions in mammalian body temperature. This finding emphasizes the importance of controlling body temperature in in vivo studies of mammalian axonal transport.

Animals↗
PubMed1980

Blockage of axonal transport induced by acute, graded compression of the rabbit vagus nerve.

Rapid axonal transport in rabbit vagus nerve was studied during and after graded nerve compression. Proteins of the rapid axonal transport were labelled by micro-injection of 3H-leucine into the nodose ganglion and the cervical vagus nerve was subjected to graded compression by a small "mini-cuff" applied directly to the exposed nerve trunk. The results showed that even slight trauma to the nerve, in this model represented by a pressure at 50 mmHg applied for two hours, may induce accumulation of axonally transported proteins at the level of compression. This transport block was, however, reversible within one day. 200 mmHg and 400 mmHg applied for two hours similarly induced a block of axonal transport persisting up to at least one and three days respectively after the compression. Time for recovery of normal transport was correlated with the magnitude of the pressure applied to the nerve. The results indicate that axons may survive, that is not undergo Wallerian degeneration, after blockage of rapid axonal transport persisting at least one day after the compression trauma.

Animals↗
PubMed1991

Stable clathrin: uncoating protein (hsc70) complexes in intact neurons and their axonal transport.

We have studied the organization of clathrin during its transport in axons. Using immunoprecipitation techniques we have confirmed earlier findings that clathrin is transported as part of slow component b, but we also detect small amounts of clathrin in fast component. As fast component is known to correspond to the transport of membraneous material, including coated vesicle membrane components, our findings suggest that some clathrin in axons undergoes transport in the form of coated membranes and that a portion of the clathrin delivered to axons and axon terminals arrives by way of fast component. The organizational form of clathrin in slow component b (SCb) was examined in more detail, as it is thought to represent a non-membrane-associated species, is relatively long-lived, and at any instant represents the major transport species in axons. We used nondenaturing immunoprecipitation methods with stringent wash procedures to identify other SCb proteins that interact with clathrin. The immunoprecipitates contained major labeled bands that corresponded to clathrin heavy and light chains, along with a prominent 70-kDa band and several minor bands that ranged in apparent Mr from 70,000 to 150,000; the 70-kDa band was shown to be the ATP-dependent uncoating protein by two-dimensional gel electrophoresis. A very similar profile of polypeptides was also immunoprecipitated from extracts of cultured neurons. The results from a variety of control immunoprecipitations, including the use of antisera preadsorbed with purified clathrin trimers or clathrin light chains, indicate that coprecipitation of clathrin and uncoating protein with the other 70,000-150,000-Da polypeptides from SCb reflects specific interactions. Including exogenous uncoating protein in the lysis buffer had no detectable effect on the levels of endogenous uncoating protein recovered in the immunoprecipitates, indicating that complexes of clathrin, uncoating protein, and the other coimmunoprecipitating SCb protein existed in the intact neurons prior to lysis. Finally, a specific and functional association is further supported by the release of uncoating protein, but not the other 70,000-150,000-Da polypeptides, from the immunoprecipitated complexes on the addition of ATP. Collectively, these observations provide the first direct evidence of interaction between clathrin and uncoating protein in intact cells, lend strong support to the concept that uncoating protein plays an intimate role in clathrin dynamics within cells, and reveal a family of 70,000-150,000-Da polypeptides that form a stable nonmembranous association with clathrin in intact cells.

Animals↗
PubMed2002

Streptozotocin-induced diabetes reduces retrograde axonal transport in the afferent and efferent vagus nerve.

Diabetes-induced alterations in nerve function include reductions in the retrograde axonal transport of neurotrophins. A decreased axonal accumulation of endogenous nerve growth factor (NGF) and neurotrophin-3 (NT-3) in the vagus nerve of streptozotocin (STZ)-induced diabetic rats was previously shown. In the current study, no changes in the NGF and NT-3 protein or mRNA levels in the stomach or atrium, two vagally innervated organs, were noted after 16 or 24 weeks of diabetes. Moreover, the amounts of neurotrophin receptor (p75, TrkA, TrkC) mRNAs in the vagus nerve and vagal afferent nodose ganglion were not reduced in diabetic rats. These data suggest that neither diminished access to target-derived neurotrophins nor the loss of relevant neurotrophin receptors accounts for the diabetes-induced alteration in the retrograde axonal transport of neurotrophins. To assess whether diabetes causes a defect in axonal transport that may not be specific to neurotrophin transport, we studied the ability of a neuronal tracer (FluoroGold, FG) to be retrogradely transported by vagal neurons of control and diabetic rats. After vagal target tissue (stomach) injections of FG, the numbers of FG-labeled afferent and efferent vagal neurons were counted in the nodose ganglion and in the dorsal motor nucleus of the vagus, respectively. After 24 weeks of diabetes, FG was retrogradely transported to more than 50% fewer afferent and efferent vagal neurons in the STZ-diabetic compared to control rats. The diabetes-induced deficit in retrograde axonal transport of FG is likely to reflect alterations in basic axonal transport mechanisms in both the afferent and efferent vagus nerve that contribute to the previously observed reductions in neurotrophin transport.

Afferent Pathways↗
PubMed1995

Functional consequences of retrograde axonal transport of receptor-bound neurotensin.

Transport mechanisms or trafficking systems in axons allow neuronal constituents to reach nerve terminals. Accordingly, presynaptic receptors undergo axonal transport through a process that is fast and bidirectional. However, axonal transport of receptors also appears to be involved in the 'flow' of information from membrane receptors to genome. The most compelling evidence that retrograde axonal transport of receptor-bound neuropeptide represents a long-distance signalling system in gene expression, discussed here by Pierre Laduron, comes from the recent observation that neurotensin injected in the striatum undergoes retrograde transport in dopaminergic neurones to the substantia nigra, where it induces in the cell bodies an increase of tyrosine hydroxylase mRNA. Although the molecular mechanisms of this remain to be elucidated, the present data suggest the existence of retrograde signal molecules, or 'third messengers', which have to be associated with synaptic or endocytotic vesicles in order to gain entry into the cell bodies, where they may modulate gene expression.

Animals↗
PubMed1979

Secretion of axonally transported neural peptides from the nervous system of Aplysia.

The possibility that proteins reaching the abdominal ganglion of Aplysia by axonal transport from the circumesophageal ganglia might be subject to secretion in that structure was examined. Transported labeled protein was found to be released from the abdominal ganglion; such release was enhanced by exposure to a high K+ medium and by electrical stimulation of the transporting axons. Stimulation of release was inhibited by lowering the Ca2+/Mg2+ ratio of the medium. The released material is predominantly of 1--2000 daltons in molecular weight and appears to have been derived from a group of transported peptides of about the same size. The possibility is raised that these data may reflect the existence of a peptidergic second-order neurosecretory pathway in this nervous system.

Animals↗
PubMed1990

Acrylamide impairs fast and slow axonal transport in rat optic system.

Effects of single and repeated doses of acrylamide on fast and slow axonal transport of radio labeled proteins following the injection of L-[4,5-3H] leucine have been studied in the optic system of male Sprague-Dawley rats. A single dose of acrylamide (100 mg/kg) had no effect, but higher concentrations (200-300 mg/kg) altered the distribution of fast axonally transported materials in optic nerves and optic tracts. Repeated doses of acrylamide (30 mg/kg/day, 5 days per week for 4 weeks) produced degeneration of tibial nerves but spared optic nerves and optic tracts. Fast axonal transport rate in optic axons was reduced by 50% (reduced to 4 mm/h from 8 mm/h) in acrylamide treated animals. Acrylamide also slowed the velocity of slow axonal transport of labeled proteins in optic axons to 1.0 mm per day from 1.3 mm per day. Since acrylamide impaired the rate of both fast and slow axonal transport in the absence of overt morphological damage, it can be concluded that deficit in axonal transport is an important factor in the pathogenesis of axonal degeneration in acrylamide neuropathy.

Acrylamide↗
PubMed1991

A fast axonally transported protein of the frog sciatic sensory axons undergoes similar qualitative changes during regeneration in vitro and in vivo.

The adult frog sciatic sensory neurons have been shown to regenerate in vitro. If a crush injury is made at the beginning of culture, regeneration starts after 3.4 days and proceeds at a rate of approximately 0.8 mm/day for several days. Two-dimensional gel electrophoresis was used to study the patterns of radiolabeled, fast axonally transported proteins during the first 7 days of regeneration. Interest was focused on one protein, referred to as rrp31 (regeneration-related protein 31), which changed in apparent pI from 4.9 to 5.3 when the outgrowth of new fibers started. The change was noticeable 3 days after injury and became prominent during day 5 of culturing. By day 7 the pI changed again, this time toward the original value. The in vitro results were supported by experiments in vivo. In this case the change occurred earlier, with a peak only 3 days after injury, after which the pI decreased. If adenosine at 1 mM was included in the culturing medium, the outgrowth of sensory axons was inhibited in a nontoxic way, and the pI changes of rrp31 were prevented. The temporal nature of the pI changes suggests a role for rrp31 in the initiation of the regeneration process.

Adenosine↗
PubMed1995

Changes in fast axonal transport in sensory neurons during tadpole metamorphosis.

Fast axonal transport of radiolabeled protein was examined in lumbar and tail dorsal root ganglion (DRG) neurons at progressive stages of bullfrog tadpole metamorphosis. Accumulation of [35S]methionine-labeled protein proximal to a lumbar peripheral nerve ligature (at a fixed distance from the DRG) increased as tadpoles advanced from premetamorphosis through prometamorphosis to metamorphic climax. The rate of increase was steeper when expressed as a percentage of protein synthesized in the neurons of origin than when expressed as a percentage of total DRG protein synthesis. Further, the increase was not secondary to a rise in protein synthesis. In contrast, fast axonal transport decreased in DRG neurons of the tail at the onset of metamorphic climax, when tail resorption is initiated. The stage-related increase in protein transport in lumbar nerves is due, at least in part, to an increased rate of transport. As determined from optically detected anterograde organelles in individual lumbar nerve axons, an approximate doubling of the fast transport rate occurred between the premetamorphic stage and metamorphic climax. In addition, the rates of organelle transport in lumbar axons of adult bullfrogs were significantly greater than in corresponding axons of tadpoles at metamorphic climax, further suggesting that organelle velocity is a developmentally regulated parameter of fast axonal transport.

Animals↗
PubMed2003

Uptake of waterborne tributyltin in the brain of fish: axonal transport as a proposed mechanism.

In previous studies, it was shown that waterborne Hg(II), Cd(II), and Mn(II) enter nerves innervating water-exposed sensory organs of fish and are transported to the brain by axonal transport. However, it is not known if organometals, such as tributyltin (TBT), can reach the brain of fish via the same route. In this work, we exposed rainbow trout (Oncorhynchus mykiss) to waterborne [113Sn]-TBT (4.2 kBq/L). Three fish were sampled after a 2-week exposure, and three others were sampled after a 2-week depuration period. Another group of four fish received an intravenous injection of [113Sn]-TBT and were sampled after 2 and 14 d. Distribution of the radiolabel was visualized and quantified by quantitative whole-body autoradiography. The brain accumulated a significant amount of 113Sn, with hot spots being found in parts receiving sensory nerves from water-exposed sensory organs, such as eminentia granulares (lateral lines organs). Labeling of the brain was also seen for i.v.-injected fish, indicating that the blood-brain barrier is not impervious to TBT or its metabolites. Nevertheless, the distribution of radioactivity in the brain was much more uniform, with no evident hot spot. Though the transfer [water --> gills --> blood stream --> blood-brain barrier --> brain] may account for a certain proportion of the radiolabel accumulation in fish brain, exposure to [113Sn]-TBT via water resulted in higher accumulation in some areas of the brain, of which the specific location strongly suggests that it was taken up in different water-exposed sensory nerve terminals and transported directly to the brain by axonal transport, as the parent compound or as a metabolite. The resulting local enhancement of the accumulation of butyltins might jeopardize the integrity of nervous system. Further work is needed to assess the toxicological significance of this process.

Animals↗
PubMedDate not supplied

Axonal transport and MR imaging: prospects for contrast agent development.

Axonal transport plays a critical role in the physiology and pathology of neurons, yet there have been virtually no clinical tools for its evaluation in human subjects. A wide variety of molecules that can act as axonal transport facilitators have been discovered and, in many cases, used to deliver labels detectable with histologic methods. Recently a number of investigators have reported preliminary success in developing intraneural contrast agents based on various versions of dextran-coated magnetite that may render magnetic resonance imaging capable of depicting axonal transport. It is not yet clear whether any clinically useful agents will eventually be developed, but there has been considerable progress in identifying design factors for such a pharmaceutical agent.

Animals↗
PubMed1999

Extracellular potassium rapidly inhibits axonal transport of particles in cultured mouse dorsal root ganglion neurites.

Changes in extracellular potassium concentration ([K+]o) modulate a variety of neuronal functions. However, whether axonal transport, which conveys materials to the appropriate destination for morphogenesis and other neuronal functions, depends on the extracellular K+ environment remains unclear. We therefore examined the effects of changes in [K+]o on axonal transport of particles visualized by video-enhanced microscopy in cultured mouse dorsal root gan-glion neurites. Increases in [K+]o (delta[K+]o > or = 2.5 mM) from control concentration (5 mM) inhibited both anterograde and retrograde axonal transport within a few minutes in a concentration-dependent manner. Conversely, removal of extracellular K+ induced the rapid facilitation of transport in both directions. These inhibitory and facilitatory responses were completely blocked by the K+ channel blocker tetraethylammonium (TEA), suggesting that the effect of changes in [K+]o involves the TEA-sensitive K+ channels. Increases in [K+]o provoked membrane depolarization in the absence and presence of TEA. Another depolarizing agent, veratridine, did not produce an effect on axonal transport. These results suggest that the extracellular K+-mediated inhibition of axonal transport does not depend on membrane depolarization. The inhibitory effect of increasing [K+]o on axonal transport was retained in calcium (Ca2+)-free extracellular medium, indicating that the inhibitory effect of extracellular K+ does not result from Ca2+ influx through voltage-dependent Ca2+ channels. In chloride (CI-)-free medium, increasing [K+]o failed to inhibit axonal transport, implying that the extracellular K+-mediated inhibition of axonal transport may be due to an increase in intracellular Cl- concentration associated with increases in the net inward movement of K+ and CI- across the membrane. Our results suggest that the extracellular K+ environment is involved in the rapid modulation of axonal transport of particles in dorsal root ganglion neurites.

Animals↗
PubMed1987

Absolute specificity for retrograde fast axonal transport displayed by lipid droplets originating in the axon of an identified Aplysia neuron in vitro.

Lipid droplets were found to form all along the axon of the giant cerebral neuron (GCN) of the sea hare Aplysia californica when the cell was placed in culture. The emission of yellow fluorescence by the droplets after exposure of the neuron to Nile red and their uniformly dark appearance in electron micrographs of axons fixed with glutaraldehyde and osmium tetroxide identified them as lipid droplets. In contrast to lipid droplets in fat cells and certain other cell types, these droplets were bounded by a membrane, indicating that the lipid droplet is a type of organelle that is membranated in some situations but not others. As observed by video-enhanced contrast-differential interference contrast microscopy, the droplets grew manyfold in place in the axon to diameters of 1-3 micron within 2-3 days. Often they formed coherent tandem arrays of 3-15 droplets. Droplets were usually essentially stationary but occasionally moved tens of microns by fast axonal transport, the largest spherical organelles to have been observed to undergo transport. They usually moved as singlets, sometimes as tandem arrays. The direction of transport was always retrograde (towards the cell body). Thus, an organelle need neither originate nor be modified in the axon terminal to be specified for retrograde transport. Whether or not an organelle is formed in the cell body might determine directionality. Alternatively, size might be a determining factor, with large organelles specified for retrograde transport.

Animals↗
PubMed1981

The influence of supraspinal impulse activity on the intra-axonal transport of transmitter-related substances in rat motor neurons.

The content and intra-axonal transport of acetylcholine (ACh) and the ACh-metabolizing enzymes choline-acetyl-transferase (CAT) and ACh-esterase (AChE) in the rat sciatic nerve were studied after various experimental procedures. The procedures involved: (1) spinal cord transection (SCT) at the thoracic level 1 day to 3 weeks prior to experiments, to abolish nerve activity of the lower motor neurons (in the lumbar intumescence-sciatic nerve) from supraspinal centres; (2) physical training for 2 h daily during 2 weeks in a rodent treadmill, to increase nerve activity from supraspinal levels; and (3) the use of selective neurotoxins to cause degeneration of descending bulbospinal monoaminergic (MA) neurons. The results of these studies demonstrate that supraspinal nerve influence can modify the axonal transport of ACh and cholinergic enzymes in the rat sciatic nerve, and that descending monoamine (MA) pathways may, at least to some extent, participate in this modulation of intraneuronal dynamics in the motor neuron. Since it has been shown by many investigators that factors which have a trophic influence on skeletal muscle cells both in vitro and in vivo are present in motor nerves and transported along the axons in a distal direction, we suggest that the synthesis and axonal transport of such factors may also be under control of supraspinal nerve activity. Therefore, it is possible that metabolic changes and dystrophy of muscles occurring in patients with lesions of the 'upper motor neuron-type' may also, in addition to other factors, be dependent on changes in intra-axonal transport of various substances in the lower motor neuron.

Acetylcholine↗