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PubMed1994

Rapid anterograde axonal transport of the cellular prion glycoprotein in the peripheral and central nervous systems.

In prion diseases, the cellular prion protein (PrPc), abundant in neurons, is converted posttranslationally into an amyloid-forming scrapie prion protein (PrPSc), which accumulates in white matter tracts and nerve terminals. The trafficking of PrPc in neurons was investigated in vivo by injecting [35S]methionine into the L4 and L5 dorsal root ganglia and the entorhinal cortices of adult rats and by tracing the movement of radiolabeled PrPc. In both paradigms, labeled 33-35-kDa PrPc was transported, within 4 h, to distal axons and nerve terminals cofractionating with proteins in the fast component. Future studies using these methods may allow us to determine whether PrPc is converted into PrpSc during axonal transport and whether PrPSc is transported in animals with prion diseases.

Animals↗
PubMed1981

Axonal transport and subcellular distribution of dopamine-beta-hydroxylase in the cod, Gadus morhua.

The axonal transport of dopamine-beta-hydroxylase (DBH; E.C. 1.14.17.1) was studied in the splanchnic nerve of the cod in vivo, and the subcellular localization of the same enzyme was studied in the chromaffin tissue from the cod head kidney. The mean rate of axonal transport for cod DBH was 18.6 mm/24 h at 10 degrees C. The mobile fraction was estimated to 22%, giving an absolute rate of transport of 85 mm/24 h at 10 degrees C. Evidence for a retrograde transport of DBH was also obtained, with an accumulation distal to a ligature of 12% of the accumulation proximal to the ligature at 3 days. DBH from the chromaffin tissue appeared to be strongly bound to the adrenergic granules, with only a small amount (ca 4%) recovered in the soluble phase.

Animals↗
PubMed1982

Block of fast axonal transport in vitro by the local anesthetics dibucaine and etidocaine.

Other investigators have shown that procaine, lidocaine and tetracaine block fast axonal transport in vitro. The present study shows that dibucaine and etidocaine also exhibit this effect. The biological material used consists of the 8th and 9th dorsal root ganglia and spinal nerves of the bullfrog; in vitro fast transport of [3H]leucine-labeled proteins is quantitated by liquid scintillation counting. Exposure of spinal nerves to dibucaine reduces the quantity of 3H-proteins which is transported to a ligature by 72% at 0.5 mM and by greater than 90% at a 1 mM concentration; since 1 mM tetracaine reduces it by 64%, dibucaine is approximately twice as potent as tetracaine at inhibiting transport. Etidocaine is less potent than tetracaine at blocking transport since 2 mM etidocaine reduces the quantity 3H-proteins at a ligature by less than 10% and 2 mM tetracaine reduces it by greater than 90%. Etidocaine is, however, more potent than lidocaine since 10 mM etidocaine reduces the quantity of 3H-proteins present at a ligature by 64% and 10 mM lidocaine reduces it by less than 10%; when tested at the same pH (6.2) as the 10 mM etidocaine solution, 2 mM tetracaine reduces radioactivity at the ligature by 49%. The ratio of concentration required to block transport (by greater than 90%) to minimum anesthetic concentration is approximately 3 for tetracaine; but this ratio is much higher for etidocaine, since etidocaine is as potent as tetracaine as a local anesthetic but approximately 5 times less potent at inhibiting fast axonal transport.

Acetanilides↗
PubMed1991

Axonal transport of two major components of the ubiquitin system: free ubiquitin and ubiquitin carboxyl-terminal hydrolase PGP 9.5.

Ubiquitin (Ub), a stress protein thought to target abnormal proteins for degradation, is present in abnormal structures that occur in neuronal perikarya and axons of degenerative diseases including Alzheimer disease. To begin to assess the role of the Ub system in the axon, we studied expression and axonal transport of Ub and other stress proteins, as well as of Ub carboxyl-terminal hydrolase PGP 9.5, in the rat visual system in normal conditions and following heat-shock (HS). In the retina, both the constitutive and inducible forms of HSPs 70 were expressed under normal conditions, while in the superior colliculus the inducible form was detected only following HS. Ub, PGP 9.5 and HSPs 70 were transported in the axon exclusively with the slow component b (SCb), known to carry cytoskeletal and cytoplasmic proteins. The exceedingly long time needed for stress proteins to reach distant axonal locales at the rate of SCb (approximately 3 mm/day) makes it unlikely that they could contribute significantly to the stress response at those sites.

Animals↗
PubMed1977

Distribution of axonal transport blockade by acute intraocular pressure elevation in the primate optic nerve head.

We studied the degree of axonal transport blockade in various areas of the optic nerve head with acute intraocular pressure (IOP) elevation in 19 squirrel monkey eyes. When IOP was raised to 20 to 50 mm. Hg for 7 hr., mild axonal transport blockade occurred in each area of the disk, most prominently in nerve fiber bundles of the superior pole. With 7 hr. IOP elevations between 50 and 90 mm. Hg, a somewhat greater degree of transport blockade occurred throughout the nerve head, although again the superior and inferior poles were somewhat more affected. The distribution of short-term transport blockade over the entire nerve head corresponds to the diffuse damage of acute glaucoma, but the pattern hints at the preference for damage near the poles of the disk seen in chronic glaucoma. However, before these results can be fully evaluated, further information is needed on axonal pathways through the optic nerve head and on the relationship between transport obstruction and ganglion cell death.

Animals↗
PubMed1984

3,4-Dimethyl-2,5-hexanedione impairs the axonal transport of neurofilament proteins.

Accumulations of neurofilaments are observed in a variety of neurological disorders, and their pathogenesis is a fundamental problem of neuropathology. 2,5-Hexanedione (HD) neurotoxicity provides an extensively studied model of axonal neurofibrillary changes in which the pathogenetic mechanisms have been conjectural. Chronic exposure to HD results in neurofilament-filled swellings in the distal regions of large axons of exposed humans and experimental animals. In this report we describe the changes produced by a potent analogue of HD, 3,4-dimethyl-2,5-hexanedione ( DMHD ), in slow axonal transport in the rat sciatic motor axons. Young rats received 0.6 mmol/kg of DMHD for 5 days before [35S]methionine was injected into the lumbar ventral horns. Slow axonal transport of the neurofilament proteins, tubulin, and selected slow component b (SCb) proteins in DMHD -treated animals was compared to the profiles found in age-matched control animals. DMHD administration reduced the rate of transport of the neurofilament proteins 75 to 90%, while tubulin and the SCb proteins were only modestly retarded. No alterations in electrophoretic mobilities of slowly transported proteins were found, nor were any proteins accelerated in transport. These findings were systematically compared to the changes produced by administration of beta,beta'- immino - dipropionitrile (IDPN) (2.0 gm/kg, i.p.), an agent known to impair neurofilament transport. Although slightly less severe, the changes produced by DMHD were nearly identical to those of IDPN. In correlative morphological studies, the neurofilamentous changes were also comparable. The results indicate that DMHD and IDPN share the capacity to interfere selectively with neurofilament transport and thereby share pathogenetic mechanisms. DMHD provides a new agent for exploration of the organization and transport of the neuronal cytoskeleton.

Animals↗
PubMed1996

Axonal transport and targeting of the t-SNAREs SNAP-25 and syntaxin 1 in the peripheral nervous system.

Axonal transport and targeting of the t-SNAREs SNAP-25 and syntaxin 1 were investigated in the rat peripheral nervous system using a stop-flow (crush) technique. In crush-operated sciatic nerves, accumulations of SNAP-25 and syntaxin 1 immunoreactivities were detected as early as 1 h after operation, indicating fast axonal transport. The amounts increased on the proximal side of the crush with time after crushing. Distal accumulations of SNAP-25, representing recycling to the cell body, were less than 10% of the proximal accumulations, but 40% for syntaxin 1, 50% for synaptobrevin II and 70% for synaptophysin. Immunoelectron microscopic studies demonstrated that SNAP-25 and syntaxin 1 are present on pleiotropic membranes within a diameter of 50 to 100 nm in axons proximal to a crush. Distal to the crush, labeling for syntaxin 1 and SNAP-25 were sparse and barely detectable, respectively. In addition, the two proteins were found in the axolemma. In nerve terminals of the spinal cord, both proteins were concentrated around small synaptic vesicles (about 50 nm in diameter), whereas only very few gold particles were observed near the presynaptic membrane or the active zones.

Animals↗
PubMed1983

Velocity of axonal transport of labeled protein is not dependent on local concentration.

The velocity of axonal transport of protein labeled with [3H]leucine was determined in rat sciatic nerve sensory axons after reversible cooling of the nerve, which provoked a local accumulation of transported material. The velocity of the wavefront of the labeled protein, as well as the slope of the wavefront, was not affected by the duration of cold-block prior to rewarming. In addition, the velocity and slope did not change as the wavefront moved distally from the site of block. In these axons, therefore, velocity of axonal transport is independent of the local concentration of rapidly transported protein.

Animals↗
PubMed1977

Release of protein from axons during rapid axonal transport: an in vitro preparation.

An in vitro system from the frog was used to study fast axonal transport and determine if transported protein is released from the axons. This preparation included the eighth and ninth dorsal root ganglia with their roots, sciatic nerve and gastrocnemius muscle. The preparation was placed in three-compartment chamber with each compartment separated by a silicone grease barrier. The dorsal root ganglia were incubated in [14C]leucine for 5 h in compartment A. The labeled protein was transported down the axon from compartment A to compartment B. The sciatic nerve in compartment B was superfused with frog Ringer. This solution was collected in hourly samples and dialyzed to remove unincoprorated leucine before counting. Incubating the ganglia in 100 microng/ml cycloheximide in frog Ringer blocked the release of labeled protein from the axon. Superfusing compartment B with solution containing 100 microng/ml cycloheximide inhibited axonal and Schwann cell protein synthesis, but did not block the release of labeled protein. It was concluded that the labeled protein released into the superfusing solution was synthesized in the ganglia and transported to the axon before release. SDS acrylamide gels were used to separate the labeled proteins. Sectioning the gels in 2 mm slices and determining the radioactivity showed that 80-85% of the counts were contained in two fast moving bands.

Animals↗
PubMed2005

Effects of a non-selective beta-blocker on adult rat anterograde axonal transport and retinal ganglion layer after increased intraocular pressure.

The aim of this study was to examine the effects of timolol in an experimental model of elevated intraocular pressure (IOP). Three episcleral veins of rats with normal IOP were cauterized. Three months later we examined the effects on anterograde axonal transport from the retinal ganglion cells (RGCs) to the superior colliculus (SC) as well as on the number of neurons in the retinal ganglion layer (RGL). These parameters were also studied in a group of rats submitted to treatment with timolol after confirming that their IOP was still raised after two weeks. After the surgical procedure, the mean IOP of the experimental eyes increased to 33.5+/-1.06 mmHg (1.25 fold compared to the control group) and three months later the IOP remained significantly elevated; however, after a long period of treatment with timolol the IOP was 14.05+/-0.81 mmHg, similar to that of the control group. In the group with normal IOP, labelling with horseradish rabbit peroxidase (HRP) at 120 minutes and 24 hours postinjection showed continuous staining from the retina to the SC. In the experimental group the optic nerve head (ONH) was completely negative, although in the group treated with timolol there was partial block of axonal transport in the ONH, in which the staining was slightly more intense. The number of neurons in the RGL, counted by immunohistochemical labelling with Neu-N, showed that in eyes with normal and elevated IOP there were 423+/-11 neurons/mm(2) and 283+/-10 neurons/mm(2), respectively. After treatment with timolol the number of neurons (331+/-10 cells/mm(2) increased compared with elevated IOP eyes, although the number did not reach that of the control group. These results indicate that treatment with timolol, started two weeks after the surgical procedure, was partially neuroprotective because the loss of neurons in the RGL was lower than in untreated animals, though not sufficient to re-establish normal axonal transport.

Adrenergic beta-Antagonists↗
PubMed1991

Local control of axonal properties by Schwann cells: neurofilaments and axonal transport in homologous and heterologous nerve grafts.

A number of axonal properties, including slow axonal transport and neurofilament phosphorylation, are altered in a mutant mouse strain with a Schwann cell deficiency, the Trembler. The Trembler phenotype is associated with poor myelination and reduced axonal caliber in the peripheral nervous system, but the genetic lesion has not yet been identified. To determine whether changes in axonal properties resulted from a direct action of Schwann cells on the axon, a segment of sciatic nerve from myelin-deficient Trembler mouse was grafted into the sciatic nerve of a normal mouse and normal axons were allowed to regenerate. Normal axons surrounded by Trembler Schwann cells are reduced in diameter, but resume their original diameter distal to the graft. Neurofilament transport was also affected locally in sciatic nerves with Trembler grafts into normal nerve. The velocity of neurofilament transport was not significantly different from controls in portions of the nerve proximal to the Trembler graft, but there was a reduction in neurofilament transport rates upon entering the Trembler graft. This was accompanied by an increase in the ratio of neurofilament over tubulin in the case of the Trembler graft, suggesting both a slowing of the neurofilament and an increase in the rate of tubulin transport. Using heterologous grafts of Trembler nerve segments into wildtype nerves, Schwann cells were shown to locally influence axonal caliber, neurofilament organization, and slow axonal transport. These observations emphasize the importance of glial cells in modulating neuronal structure and functions, as well as focusing attention on the role of glia in the etiology of neuropathologies that alter the neuronal environment.

Animals↗
PubMed1991

Retrograde axonal transport of locally synthesized phosphoinositides in the rat sciatic nerve.

Although autoradiography has demonstrated local incorporation of [3H]inositol into axonal phospholipids after intraneural injection, retrograde axonal transport of phosphatidylinositol has only been demonstrated after injection of lipid precursor into the cell body regions (L4 and L5 dorsal root ganglia) of the sciatic nerve. We now report the retrograde axonal transport of inositol phospholipids synthesized locally in the axons. Following microinjection of myo-[3H]inositol into the rat sciatic nerve (50-55 mm distal to L4 and L5 dorsal root ganglia), a time-dependent accumulation of 3H label occurred in the dorsal root ganglia ipsilateral to the injection site. The ratio of dpm present in the ipsilateral dorsal root ganglia to that in the contralateral dorsal root ganglia was not significantly different from unity between 2 and 8 h following isotope injection but increased to 10-12-fold between 24 and 72 h following precursor injection. By 24 h following precursor injection, the ipsilateral/contralateral ratio of the water-soluble label in the dorsal root ganglia still remained approximately 1.0, whereas the corresponding ratio in the chloroform/methanol-soluble fraction was approximately 20. The time course of appearance of labeled lipids in the ipsilateral dorsal root ganglia after injection of precursor into the nerve at various distances from the dorsal root ganglia indicated a transport rate of at least 5 mm/h. Accumulation of label in the dorsal root ganglia could be prevented by intraneural injection of colchicine or ligation of the sciatic nerve between the dorsal root ganglia and the isotope injection site. These results demonstrate that inositol phospholipids synthesized locally in the sciatic nerve are retrogradely transported back to the nerve cell bodies located in the dorsal root ganglia.

Animals↗
PubMed1988

Heat stress induces changes in protein synthesis and fast axonal transport in bullfrog sensory neurons.

The effects of heat stress on protein synthesis and fast axonal transport were examined in an in vitro bullfrog primary afferent neuron preparation. The magnitude of effect was determined for individual [35S]methionine-labelled protein species separated via two-dimensional gel electrophoresis. Elevation of temperature of the preparation from 18 degrees C to 33 degrees C caused a transient inhibition of synthesis of non-heat-shock proteins, whereas the synthesis of a 74,000-dalton protein increased to 927% of controls after 4 h. Similar prolonged stress conditions had no effect on the relative abundance of 36 individual, newly synthesized proteins undergoing fast axonal transport. A dramatic exception was represented by a 55,000-dalton glycoprotein whose fast transport was increased to 291% of control. The increase in transport of this protein during a time when synthesis and transport of other non-heat-shock proteins were not enhanced suggests that it may play a unique role in the early cellular events that mediate survival or thermotolerance in the neuron.

Animals↗
PubMed1987

Cytotypic differences in the protein composition of the axonally transported cytoskeleton in mammalian neurons.

Many of the structural and functional differences between axons are thought to reflect underlying differences in the biochemical composition and dynamic aspects of the axonal cytoskeleton and cytomatrix. In this study we investigated how the composition of the 2 slow components of axonal transport, SCa and SCb, which convey the cytoskeleton and cytomatrix, differs in axons that are structurally and functionally distinct. For this comparison we analyzed axons of retinal ganglion cells in the optic nerve (ON), axons of dorsal root ganglion (DRG) cells, and axons of ventral motor neurons (VMN) in adult rats. 35S-Methionine-labeled proteins transported with the peak of SCa and SCb were analyzed using high-resolution 2-dimensional polyacrylamide gels (2D-PAGE) and fluorography, and the amounts of major SCa and SCb proteins were quantified. The polypeptide composition of both SCa and SCb was found to be largely similar in DRG and VMN axons, but major qualitative as well as quantitative differences between these axons and ON axons were found. Notable among these were higher ratios of neurofilament protein to tubulin in SCa in DRG and VMN axons compared to ON axons, and significantly larger amounts of 2 microtubule-associated proteins relative to tubulin in SCa of ON axons than in both VMN and DRG axons. Tubulin was the major SCb protein in VMN and DRG axons, but it was not present in SCb in ON axons. Additionally, relatively larger amounts of 2 metabolic enzymes, creatine phosphokinase and nerve-specific enolase, were present in SCb in ON axons than in DRG or VMN axons. The results indicate that significant biochemical heterogeneity among different types of axons can be identified by examining the slow components of axonal transport.

Actins↗
PubMed1998

Alterations in retrograde axonal transport in optic nerve of type I and type II diabetic rats.

Clinical and electrophysiological examinations have yielded visual pathway function abnormalities in both humans and animal models with diabetes mellitus (DM). However, subclinical involvement of the optic nerve has not yet been fully investigated. In this study, we demonstrated the different impairments in retrograde axonal transport occurring in selective retinal ganglion cells (RGCs) of Type I and II diabetic rats. Rats were injected with streptozotocin (STZ) to induce Type I DM. The Otsuka Long-Evans Tokushima Fatty (OLETF) rats represented the Type II DM group. The STZ-induced (Type I) diabetic rats had low body weights and significant elevations in blood glucose levels compared with the age-matched control rats. On the contrary, the OLETF rats (Type II) had high body weights and significant elevations in blood glucose concentrations compared with the age-matched controls. Fluoro-Gold (FG) was injected into the bilateral dorsal lateral geniculate nucleus. Accumulation of FG in large and medium type RGCs in STZ-induced diabetic rats was significantly decreased compared with the controls. However, the accumulation of FG in RGCs of OLETF rats did not show a significant decrease compared with the controls. Our findings suggest that, within the time frame of study, retrograde axonal transport impairment of large and medium type RGCs in the STZ-induced (Type I DM) diabetic rats was greater than in the OLETF (Type II DM) diabetic rats. Impairment of retrograde axonal transport in Type I diabetes may precede or be a consequence of metabolic dysfunctions in the large and medium-sized RGCs eventually leading to optic nerve atrophy.

Animals↗
PubMed1980

Consequences of axonal transport blockade induced by batrachotoxin on mammalian neuromuscular junction I. Early pre- and postsynaptic changes.

Subperineural injections of batrachotoxin (BTX) (1.86 X 10-12 or 9.3 X 10-12 mol) were made into the peroneal nerve at 10-12 or 33-35 mm from the entrance of the nerve into the extensor muscle of the rats. Measurements of fast axonal transport in the nerve and the resting membrane potential (RMP) from the surface fibers of the extensor muscle were made at intervals up to 18 h after injection of the toxin. The transport of 3H-labeled proteins and nerve conduction were blocked almost instantaneously by either dose of toxin. At 18 h some radioactive material distal to the BTX injection site could be seen, indicating partial recovery in fast axonal transport. Membrane depolarization of about 4 mV was evident in the surface fibers of the extensor muscle 50 min after injecting BTX in the peroneal nerve at a distance of 10 mm from the muscle. If the toxin was injected into the nerve at a farther site (33-35 mm), the onset of muscle membrane depolarization occurred at 120 min. The muscle membrane depolarization seen after injection of BTX at these two sites in the nerve was not a result of the toxin acting directly on the muscle nor was the depolarization reversibly by bath applied tetrodotoxin (TTX). Similar subperineural injections of TTX (6.3 X 10-9 mol) into peroneal nerve failed to cause any membrane depolarization in the extensor muscle even up to 18 h although the leg on the injected side was paralyzed in the same fashion as was the one with BTX. Membrane potential consistently recovered at 18 h in all BTX-injected animals although spontaneous release of transmitter had completely ceased at this time. These results conclusively demonstrate the fact that blockade of axonal transport by BTX and not suppression of electrical activity in the nerve caused by this agent is responsible for the early membrane depolarization of surface fibers of the extensor muscle. Thus the notion that resting membrane potential is under neurotrophic control is further supported. Muscle inactivity produced by paralysis of the affected limb alone apparently plays very little role in the onset of muscle depolarization and cessation of transmitter release.

Animals↗
PubMed1989

Axonal transport studied in a single vertebrate neuron: the giant electromotor neuron of the electric catfish, Malapterurus electricus.

Axonal transport was studied using a single vertebrate neuron, the giant electromotor neuron of the electric catfish, Malapterurus electricus. The electric organs of this strongly electric fish are innervated by two neurons whose axons form one electric nerve each. After injection of [35S]methionine into the spinal cord at the level of the two perikarya radioactively labelled material is exported by fast flow as a small wave with a velocity of 5.8 mm/h and a somal release time of 91 min (29 degrees C). Slow flow investigated between 15 and 39 days had a velocity of 1.36 mm/d at 29 degrees C. Analysis of radiolabelled proteins by polyacrylamide gel electrophoresis revealed different patterns of labelling between slow and fast flow. The relative molecular mass of the two major proteins labelled on slow flow correspond to actin and tubulin. Labelled proteins of higher relative molecular mass may correspond to neurofilament proteins. Our results suggest that this vertebrate single-neuron and single-axon system can be used successfully for axonal transport studies.

Animals↗
PubMed1980

Fast axonal transport of foreign transmitters in an identified serotonergic neurone of Aplysia californica.

1. Radioactively labelled compounds, several of which are neurotransmitters, were injected with pressure into the soma of the serotonergic giant cerebral neurone (g.c.n.) of Aplysia californica. The compounds injected were [3H]dopamine, [3H]DL-octopamine, [3H]histamine, [3H]gamma-aminobutyric acid and [3H]choline. 2. Substantial amounts of radioactivity appeared in the axons of the g.c.n. with all of the injected compounds. Except for [3H]choline, the amounts were similar to the amount appearing when [3H]serotonin is injected. 3. The biogenic amines, [3H]dopamine, DL-[3H]octopamine and [3H]histamine, all moved in the axon at velocities similar to that of [3H]serotonin. In contrast, the radioactivity in axons of cells injected with [3H]gamma-aminobutyric acid and [3H]choline moved much more slowly. In addition, the shapes of the spatial distributions of radioactivity in the axons of cells injected with the biogenic amines resembled that obtained when [3H]serotonin is injected. This distribution is characteristic of fast axonal transport. The spatial distributions of radioactivity in the axons of cells injected with [3H]gamma-aminobutyric acid and [3H]choline were markedly different. We thus conclude that [3H]dopamine, DL-[3H]octopamine and [3H]histamine move by fast axonal transport, whereas the radioactivity in the axons of cells injected with [3H]gamma-aminobutyric acid and [3H]choline does not. 4. Injection of large amounts of dopamine and octopamine reduced the export into the axon of [3H]serotonin injected into the same cell. Large amounts of choline did not reduce export of [3H]serotonin. We conclude that the biogenic amines compete with serotonin for the vesicular storage site and that they move by fast transport because they are sequestered by the serotonergic storage vesicle. 5. The specificity of uptake into the storage vesicle as assayed with this in vivo system is similar to the specificity of uptake into aminergic vesicles as previously studied in vitro.

Animals↗