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PubMed1991

Lack of retrograde axonal transport of the heparin-binding growth factors by chick ciliary neurones.

In view of the likelihood that the heparin-binding growth factors of fibroblast growth factors are neurotrophic for the neurones of the chick ciliary ganglion a study has been made of the retrograde axonal transport of the acidic and basic fibroblast growth factors by these neurones. No high capacity retrograde axonal transport of these molecules was seen. The amount of transport was equivalent to the low level seen with many proteins such as horse radish peroxidase or bovine serum albumin rather than the convincing transport seen for nerve growth factor in the sympathetic system. The iodinated proteins retained their ability to bind to neuronal receptors. Thus, if the fibroblast growth factors are neurotrophic in the ciliary ganglion, they may exert their action by mechanisms other than the retrograde axonal transport of the factor itself.

Animals↗
PubMed1986

Changes in components of fast axonally transported proteins in the optic nerves of diabetic rabbits.

Proteins synthesized in retinal ganglion cells were labeled with 35S-methionine or 3H-leucine to the vitreous cavity, and the components of fast axonally transported proteins were studied in 20 nerves of 10 normal rabbits and 34 nerves of 17 alloxan-induced diabetic rabbits. Proteins in the optic nerves were separated by SDS-polyacrylamide gel electrophoresis, and axonally transferred proteins were studied by fluorography. In diabetic animals, the axonally transported radioactivity was one-fifth that of the controls. In the fluorographic spectrum of 35S-methionine-labeled proteins, relative proportion of 120kDalton(D)-proteins were increased by 43%, and 29kD proteins were decreased by 65% in diabetic rabbits. Relative proportion of other proteins, such as 24k, 36k, 68k, 150k and 180kD, were the same in control and diabetic rabbits. The quantitative reduction and change in spectrum of fast axonally transported proteins are compatible with the vulnerability and dysfunctions of nerve fibers in diabetic patients.

Animals↗
PubMed1995

Structural analysis of glycosaminoglycans derived from axonally transported proteoglycans in regenerating goldfish optic nerve.

Structural characteristics of glycosaminoglycans (GAGs) derived from axonally transported proteoglycans (PGs) were compared in 21 days regenerating and intact goldfish optic tracts. Twenty one days following unilateral optic nerve crushes, fish received intraocular injections of 35SO4. Eight hours post injection, tracts were removed and the 35SO4-labeled GAGs, chondroitin sulfate (CS) and heparan sulfate (HS), isolated. The HS from regenerating optic tracts had a DEAE elution profile indicative of decreased charge density, while heparitinase treatment of HS followed by Sephadex G50 analysis of the resulting fragments showed a change in the elution pattern, suggesting reduced overall sulfation. HPLC analysis of HS disaccharides revealed a difference in the sulfation pattern of regenerating tract HS, characterized by the reduced presence of tri-sulfated disaccharides. Other structural features, such as the sizes of CS and HS, and the sulfation of CS, showed no changes during regeneration. These results indicate that changes in the structure of axonally transported HS accompany regeneration of goldfish optic axons.

Animals↗
PubMed1994

Axonal transport of herpes simplex virions to epidermal cells: evidence for a specialized mode of virus transport and assembly.

To examine the transmission of herpes simplex virus (HSV) from axon to epidermal cell, an in vitro model was constructed consisting of human fetal dorsal root ganglia cultured in the central chamber of a dual-chamber tissue culture system separated from autologous skin explants in an exterior chamber by concentric steel cylinders adhering to the substratum through silicon grease and agarose. Axons grew through the agarose viral diffusion barrier and terminated on epidermal cells in the exterior chamber. After inoculation of HSV onto dorsal root ganglia, anterograde axonal transport of glycoprotein and nucleocapsid antigen was observed by confocal microscopy to appear in exterior chamber axons within 12 h and in epidermal cells within 16 h, moving at 2-3 mm/h. Although both enveloped and unenveloped nucleocapsids were observed in the neuronal soma by transmission electron microscopy, only nucleocapsids were observed in the axons, closely associated with microtubules. Nodule formation at the surface of HSV-infected axons, becoming more dense at the axon terminus on epidermal cells, and patches of axolemmal HSV glycoprotein D expression were observed by scanning (immuno)electron microscopy, probably representing virus emerging from the axolemma. These findings strongly suggest a specialized mode of viral transport, assembly, and egress in sensory neurons: microtubule-associated intermediate-fast anterograde axonal transport of unenveloped nucleocapsids with separate transport of glycoproteins to the distal regions of the axon and assembly prior to virus emergence at the axon terminus.

Antibodies, Monoclonal↗
PubMed1985

AVEC-DIC and electron microscopic analyses of axonally transported particles in cold-blocked squid giant axons.

Anterogradely and retrogradely transported membranous organelles were analysed separately by focally cooling axons (cold-blocking) for 2-4 h. Video-enhanced differential interference contrast light microscopy (AVEC-DIC) and dark field light microscopy showed that particles accumulated in large numbers on both the anterograde and the retrograde sides of the cold-block and that the accumulated particles resumed their transport when the preparation was rewarmed to 18 degrees C. The particles accumulated in files on both sides of the cold-block suggesting that particles move along linear pathways in the axoplasm. Comparisons of the results obtained by AVEC-DIC light microscopy with those obtained by electron microscopy indicate that the AVEC-DIC method is capable of detecting all of the different types of rapidly transported membranous organelles, including the smallest (35-80 nm) vesicles that move anterogradely. Electron microscopic analyses of the transported particles demonstrate that the anterogradely transported organelles are structurally distinct from those that are transported retrogradely. The anterogradely transported particles consisted of normal mitochondria and small (35-80 nm) tubulovesicular profiles. By contrast, the retrogradely transported particles were 150 nm or larger and they often contained complex membranous inclusions. The largest retrogradely transported particles appeared to be degenerating mitochondria. The results are consistent with the hypothesis that the direction of organelle movement is related to the physiological state of the organelle. That is, organelles containing newly synthesized membrane components move primarily anterogradely and organelles that contain transformed and degraded membrane components move retrogradely.

Animals↗
PubMed1988

Association of axonally transported heparan sulfate with isolated synaptic plasma membrane.

Studies on isolated synaptic plasma membranes (SPM) have detected little if any heparan sulfate or other glycosaminoglycans (GAGs), while more recent studies employing proteoglycan antibodies have localized heparan sulfate proteoglycan in presynaptic plasma membrane of intact tissue. To further address the issue of proteoglycans in synaptic plasma membrane, we have investigated the possible presence of axonally transported GAGs in SPM isolated from the goldfish optic tectum. SPMs isolated from tecta following rapid axonal transport of 35SO4 labeled molecules down the optic nerve, showed specific radioactivity approximately two-fold higher than the starting homogenate. Treatment of the transport labeled SPM with the enzyme heparitinase liberated 21% of the radioactivity, indicating the presence of a significant fraction of transported label in heparan sulfate. In a separate series of experiments a GAG fraction was isolated from transport labeled SPM and was found to consist of heparan sulfate containing 28% of transported radioactivity. Chondroitin (4 or 6) sulfate, which undergoes axonal transport in the goldfish optic system, was not found associated with SPM. Taken together the results support immunological evidence for the presence of heparan sulfate proteoglycans in presynaptic plasma membrane.

Animals↗
PubMed2005

Molecular motors implicated in the axonal transport of tau and alpha-synuclein.

Tau and alpha-synuclein are both proteins implicated in the pathology of neurodegenerative disease. Here we have investigated the mechanisms of axonal transport of tau and alpha-synuclein, because failure of axonal transport has been implicated in the development of several neurodegenerative disorders. We found that the transport of both of these proteins depend on an intact microtubule- but not actin-cytoskeleton, and that tau and alpha-synuclein both move at overall slow rates of transport. We used time-lapse video microscopy to obtain images of live neurons that had been transfected with plasmids expressing proteins tagged with enhanced green fluorescent protein. We found that particulate structures containing tau or alpha-synuclein travel rapidly when moving along axons but spend the majority of the time paused, and these structures have similar characteristics to those previously observed for neurofilaments. The motile particles containing tau or alpha-synuclein colocalise with the fast-transporting molecular motor kinesin-1 in neurons. Co-immunoprecipitation experiments demonstrate that tau and alpha-synuclein are each associated with complexes containing kinesin-1, whereas only alpha-synuclein appears to interact with dynein-containing complexes. In vitro glutathione S-transferase-binding assays using rat brain homogenate or recombinant protein as bait reveals a direct interaction of kinesin-1 light chains 1 and 2 with tau, but not with alpha-synuclein. Our findings suggest that the axonal transport of tau occurs via a mechanism utilising fast transport motors, including the kinesin family of proteins, and that alpha-synuclein transport in neurons may involve both kinesin and dynein motor proteins.

Actins↗
PubMed1982

Inhibition of fast axonal transport in vitro by tetracaine: an increase in potency at alkaline pH, and no change in potency in calcium-depleted nerves.

Some of the present in vitro experiments compare the degree of inhibition of fast axonal transport produced by tetracaine at neutral and at alkaline pH. In desheathed spinal nerves from bullfrog, 0.5 mM tetracaine reduced the quantity of [3H]leucine-labeled proteins which were transported to a ligature by 43% at pH 7.2 and by 96% at pH 8.2; separate experiments established that transport was not affected by the pH change in the absence of tetracaine. The relationship between pH and transport-blocking potency of tetracaine (pKa 8.2) is such that the local anesthetic is more potent when more uncharged form of the molecule is present; this may reflect the easier penetration across the axonal plasma membrane by the uncharged form of the tetracaine molecule. The axonal smooth endoplasmic reticulum has been attributed the function of a calcium reservoir, and it appeared possible that local anesthetics could block axonal transport by releasing calcium from this structure. However, the inhibition of transport produced by 1 mM tetracaine (pH 7.1) in sheathed nerves was approximately 80% both in nerves with a lower than normal calcium content (47% of normal) and in nerves with a normal calcium content; this result does not support the hypothesis that inhibition of axonal transport by local anesthetics is mediated by an increase in intracellular free Ca2+, but does not rule out the hypothesis either.

Animals↗
PubMed1979

On the kinetics and maximal capacity of the system for rapid axonal transport in mammalian neurones.

1. Rabbit peroneal nerves were incubated in vitro in two-compartment chambers. Step-gradients of temperature were established so that the proximal part of each nerve was slightly warmer than the distal part. After incubation, the distribution of dopamine-beta-hydroxylase (DBH) activity along the nerves was examined as an indication of the behaviour of rapid transport in adrenergic axons. 2. With temperature gradients of 5 and 8 degrees C, transport velocity in the proximal regions was expected from previous work to be, respectively, 1.5 and 2 times faster than in the distal regions. Exposing nerves to these gradients induced a significant increment in the concentration of DBH activity, beginning at the boundary between regions. This increment was up to 50% of the normal activity and it propagated distally at the velocity expected for transport at the local temperature. 3. A temperature gradient of 13 degrees C was expected to produce a threefold difference in transport velocity between proximal and distal regions. This gradient produced a slightly larger increment of DBH activity propagating distally, again at the expected velocity. However there was also a disproportionate accumulation of enzyme activity at the boundary between regions. Further increases in the temperature gradient did not enhance the size of the propagating increment but only the rate at which enzyme accumulated at the temperature boundary. 4. It was concluded that adrenergic nerves can transport between two and three times as much material per unit time as they normally do. The ability to increase the flux of material appeared to depend on increases in the concentration of material in motion. There was no indication that such increases led to significant changes in the velocity of transport.

Adrenergic Fibers↗
PubMed2000

Retrograde axonal transport impairment of large- and medium-sized retinal ganglion cells in diabetic rat.

PURPOSE: Several abnormalities in visual pathway functions in diabetic humans and animals have been reported. We demonstrated retrograde axonal transport impairment in retinal ganglion cells of streptozotocin-diabetic rats. METHODS: Diabetes was induced in male Wistar albino rats by intraperitoneal injection of streptozotocin. Three months after the induction of diabetes, fluoro-gold was injected into the dorsal lateral geniculate nucleus. Percentages of fluoro-gold-labeled large-, medium- and small-sized retinal ganglion cells per total population were calculated in wholemount retinas of diabetic and control rats. The same sections were stained with cresyl violet and each retinal ganglion cell type evaluated by light microscopy. RESULTS: Although a quantitative decrease in the population of each retinal ganglion cell type was not observed, mean percentages of fluoro-gold-labeled large- and medium-sized retinal ganglion cells per total population were significantly decreased in diabetic rats compared with controls. CONCLUSIONS: Our results suggest that diabetes affects the retrograde axonal transport in large- and medium-sized retinal ganglion cells despite the absence of morphological changes in the perikaryon and decrease in total cell population. Diabetes-induced impairment of retrograde axonal transport in large- and medium-sized retinal ganglion cells precede optic nerve involvement. However, this may merely be a consequence of metabolic changes in diabetic states.

Animals↗
PubMed1999

Axonal transport is inhibited by a protein kinase C inhibitor in cultured isolated mouse dorsal root ganglion cells.

We investigated roles of protein kinase C (PKC) and Ca2+/calmodulin-dependent protein II (CAM II) kinase activities in the maintenance of axonal transport in cultured isolated mouse dorsal root ganglion (DRG) cells. Video-enhanced microscopic recordings revealed that the PKC inhibitor chelerythrine (1 microM) reduced anterograde and retrograde axonal transport, while the CAM II kinase inhibitor KN-62 (10 microM) had no effect. Morphological observation showed that neurite growth was prevented by the presence of chelerythrine (1 microM). From these results, we conclude that PKC activity is required to maintain axonal transport and thereby neurite growth.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1985

CMP-sialic acid, the sole sialosyl donor, is intra-axonally transported.

N-Acetyl-D-[6-3H]mannosamine was injected into the 9th dorsal root ganglion of Xenopus laevis and the intra-axonal transport of chloroform/methanol-soluble radioactivity was analyzed using thin-layer chromatography coupled with fluorography. Three radioactive groups were distinct in consecutive segments of the sciatic nerve. The first is due to N-acetyl-D-mannosamine itself which labels the nerve uniformly, but does not seem to migrate within axons. The second group, representing most probably CMP-sialic acid, migrates at about 8 mm/day at 15 degrees C. The third is a species of ganglioside uniquely present in the frog nerve, and this migrates at 1-3 mm/day. Our demonstration of the intra-axonal transport of CMP-sialic acid affords direct support to the contention that sialosylation of the ganglioside can occur in axon terminals.

Animals↗
PubMed2004

Cdk5 regulates axonal transport and phosphorylation of neurofilaments in cultured neurons.

Phosphorylation has long been considered to regulate neurofilament (NF) interaction and axonal transport, and, in turn, to influence axonal stability and their maturation to large-caliber axons. Cdk5, a serine/threonine kinase homologous to the mitotic cyclin-dependent kinases, phosphorylates NF subunits in intact cells. In this study, we used two different haptenized NF subunits and manipulated cdk5 activity by microinjection, transfection and pharmacological inhibition to monitor the effect of Cdk5-p35 on NF dynamics and transport. We demonstrate that overexpression of cdk5 increases NF phosphorylation and inhibits NF axonal transport, whereas inhibition both reduces NF phosphorylation and enhances NF axonal transport in cultured chicken dorsal-root-ganglion neurons. Large phosphorylated-NF 'bundles' were prominent in perikarya following cdk5 overexpression. These findings suggest that Cdk5-p35 activity regulates normal NF distribution and that overexpression of Cdk5-p35 induces perikaryal accumulation of phosphorylated-NFs similar to those observed under pathological conditions.

Animals↗
PubMed1981

Are axonally transported proteins released from sciatic nerves?

A recent report by Hines and Garwood claimed a significant release of axonally transported proteins from frog sciatic nerve into a surrounding solution. In the present study no significant release of axonally transported protein from frog sciatic nerves was detected with more stringent control for non-axonal sources of released protein.

Animals↗
PubMed1977

Differences in the composition of the polypeptides deposited in the axon and the nerve terminals by fast axonal transport in the garfish olfactory nerve.

Proteins transported by the fast wave of axonal transport have been shown to be deposited both in the axon and in the nerve terminals. Differences in the nature of the molecules deposited in these two areas were studied in the garfish olfactory system. In order to avoid analysis of transported molecules in two different types of tissue like the olfactory nerve and the olfactory bulb, the study was conducted (1) by comparing the composition of the moving crest of radioactivity at two different points along the nerve: when the crest enters the axon and when it reaches a distance of approximatively 5 cm from the nerve endings, (2) by determining the composition of the molecules remaining in the axon behind the moving crest. Three subcellular fractions (two membranous fractions and a mitochondrial pellet) were investigated. In both membranous fractions the majority of the polypeptides deposited in the axon ranged from 50 to 150,000 daltons. No outstanding peak of radioactivity was found in either fraction. Radioactivity was relatively evenly distributed among the various polypeptides. In the lightest membranous fraction, however, a peak (mol. wt., 54-58,000) was more particularly deposited in the axon. The opposite situation was found for the molecules moving toward the synapses: transported radioactivity was concentrated in a few distinct polypeptides, while the others were significantly less labeled. Three peaks were found in the lightest membranous fraction (mol. wt., 35,000, 54-58,000 and 126,000). Only two peaks were determined in the heaviest fraction (mol. wt., 58,000 and 126,000). The 126,000 mol. wt. peak increases with distance in both membranous fractions from 9 to 12% of the total radioactivity and moves mainly toward the synapses. The 35,000 mol. wt. polypeptide presented some interesting properties: it was found in larger quantities in the lightest membranous fraction; labeling was very poor in the heaviest membranous fraction, and finally this polypeptide appeared to be largely transported to the synapses. Results concerning the polypeptide composition and the composition of the transported molecules indicated that the lightest fraction may contain more synaptosomal material. From this study it appears that most transported polypeptides are distributed in both the axon and the nerve terminals, but that the percentage delivered to each area varies. A few distinct polypeptides on the contrary are more selectively transported to the synapses and are even differently localized in subcellular fractions.

Animals↗
PubMed1979

Retrograde axonal transport of specific macromolecules as a tool for characterizing nerve terminal membranes.

The uptake of macromolecules by nerve terminals which is followed by retrograde axonal transport seems to occur by two different mechanisms, a specific and a nonspecific one. The nonspecific uptake depends on the presence of macromolecules (e.g., horseradish peroxidase) in the vicinity of the nerve terminals at very high concentrations and is enhanced by neuronal activity. In contrast, the specific uptake and subsequent retrograde axonal transport becomes apparent at much lower concentrations of the appropriate macromolecules, depends on the affinity of these ligands for specific binding sites on the surface of the neuronal membrane, and is independent of neuronal activity. The fact that lectins and some bacterial toxins bind to specific membrane glycoproteins or glycolipids allows conclusions to be drawn regarding qualitative and even quantitative aspects of the composition of the plasma membrane of the nerve terminals. 125I-labelled nerve growth factor (NGF), tetanus toxin, cholera toxin, wheat germ agglutinin (WGA), ricin II, phytohemagglutinin (PHA), and concanavalin A (ConA) were injected into the anterior eye chamber of rats where they were taken up by adrenergic nerve terminals and transported retrogradely to the superior cervical ganglion. The saturation of the uptake-transport found for NGF, WGA, choleragenoid and an atoxic binding-fragment of tetanus toxin indicates that limited numbers of binding sites, which showed also different affinities, are present for each ligand on the membrane of the nerve terminals. Competition experiments showed that the binding sites for the ligands investigated are largely independent. Two different classes of binding sites (high affinity--low capacity and intermediate affinity--intermediate capacity) seem to be involved in the saturable retrograde axonal transport of NGF. In contrast, WGA seems to have only a single class of binding-uptake sites with high capacity and relatively low affinity. Strong evidence for positive cooperativity was obtained for the uptake and subsequent transport of the tetanus toxin fragment.

Animals↗
PubMed1980

Evidence against the smooth endoplasmic reticulum as a continuous channel for the retrograde axonal transport of horseradish peroxidase.

The involvement of the axonal smooth endoplasmic reticulum as a channel for the retrograde axonal transport of horseradish peroxidase (HRP) has been tested by analysing serial sections of 52 HRP-positive organelles in chick optic nerves. The enzyme marker was injected in the posterior, contralateral optic tectum 10 h before fixation of young chicks. The two optic nerves, retinas and optic tecta were incubated for electron microscopic demonstration of HRP. Thin sections of the retinas and tecta and serial thin sections of the optic nerves were studied in some cases with the aid of a goniometer. Of the 52 organelles, 42% had a tubular shape, 46% were oval and 12% were multivesicular bodies. None of the organelles was found to have continuities with other membranous structures, including tubules or cisternae of the smooth endoplasmic reticulum. In 10 cases, the smooth endoplasmic reticulum was followed in serial sections over a length of up to 4 micrometer. In every case, the reticulum appeared to form a continuous system although some tubular extensions apparently ended blindly near other organelles. In neither the 10 series of serial sections nor in any other individual micrographs did any recognizable profile of the smooth endoplasmic reticulum contain HRP. Measurements of the thickness of the membranes of HRP-containing organelles, of the smooth endoplasmic reticulum and of plasmalemma were made, since these membranes have been distinguished on the basis of their thickness in other cells. The plasmalemma in the axons was about 20% thicker than that of the smooth endoplasmic reticulum, and about 9% thicker than that of HRP-labeled organelles. The membrane of the smooth endoplasmic reticulum and HRP-organelles could also be distinguished by this means. It is concluded that in chick retinal ganglion cell axons, HRP is not transported in a retrograde direction via a continuous channel of smooth endoplasmic reticulum.

Animals↗
PubMed1992

Slow axonal transport is impaired by intrathecal 2,5-hexanedione.

Anterograde axonal transport was studied in a new model of hexacarbon neuropathy, in which neurofilament (NF)-containing giant axonal swellings are induced proximally in the spinal nerve roots of rats by intrathecal injection of 2,5-hexanedione (2,5-HD). Decreased transport velocity of the NF-containing slow component a (SCa) was demonstrated in 2,5-HD-treated animals, in contrast to studies demonstrating increased velocity of SCa in proximal parts of the axon in systemic 2,5-HD intoxication, which causes distal axonal swellings. Other components of anterograde transport were unaffected. In systemic 2,5-HD toxicity, velocity of NF transport increases in the proximal axon, but may decrease distally, where it is difficult to study. Decreased NF transport is likely to be responsible for the formation of axonal swellings, since they occur preterminally rather than at the axon terminal as would be expected if increased NF transport were the cause. Covalent modification of proteins provides a possible mechanism by which 2,5-HD affects axonal transport, and the effect may be facilitatory or inhibitory depending on the level and duration of exposure of the NF to the toxin.

Animals↗