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PubMed1980

The composition and organization of axonally transported proteins in the retinal ganglion cells of the guinea pig.

We labeled the proteins of guinea pig retinal ganglion cells with [35S]methionine and analyzed the axonally transported polypeptides by means of sodium dodecyl sulfate gel electrophoresis. Five groups of transported polypeptides could be distinguished by their characteristic times of initial appearance in segments of the axons of the retinal ganglion cells. The times of initial appearance of the groups corresponded to maximum transport velocities ranging from greater than 200 mm/day to 0.5 mm/day. We directly compared these transported polypeptides to polypeptides undergoing axonal transport in the retinal ganglion cells of the rabbit. Electrophoretically similar polypeptides were transported at the same relative velocities in the two animals. Our results lead to the following conclusions. (1) The basic composition and organization of axonally transported proteins is probably a general constant feature of mammalian retinal ganglion cells, implying that the correct organization is important for the proper functioning of these neurons. Therefore, the results obtained by the analysis of individual model systems should have general significance. (2) Four discontinuities in the transport process (in addition to the 5 discontinuities represented by the major transport groups) were revealed by a consideration of subtle differences between the rabbit and guinea pig, as well as differences in the rate of disappearance of label from individual polypeptides within each transport group. (3) The guinea pig should provide a useful model system for studying axonal transport, especially for immunological studies, since antibodies against axonally transported proteins of the guinea pig can be conveniently prepared in the rabbit. (4) While the structure (as reflected by electrophoretic mobility) of most major axonally transported polypeptides appears to be conserved over the evolutionary period (about 30 million years) separating two orders of mammals, the electrophoretic mobility of one neurofilament-associated polypeptide, H, was abnormally variant between the two species.

Animals↗
PubMed1987

Fast axonal transport in amyotrophic lateral sclerosis: an intra-axonal organelle traffic analysis.

Fast transport of intra-axonal organelles was studied in motor nerve from amyotrophic lateral sclerosis (ALS) patients. Organelle traffic in ALS nerves demonstrated a significant increase in anterograde mean speed, while retrograde mean speed was decreased compared with that of controls. Retrograde traffic density (organelles per unit time) was also significantly decreased in the ALS specimens. Anterograde transport machinery is therefore intact and may be responding to the increased physiologic demand of larger motor units. Diminished retrograde speed and organelle traffic density are consistent with a defect in retrograde transport and could impair communication between axon terminals and perikarya.

Amyotrophic Lateral Sclerosis↗
PubMed1983

Influence of antiglaucoma drugs on axonal transport in the optic nerve.

Tritiated leucine injected into the vitreous of experimental animals was used for detection of the dynamics of axonal transport in the optic nerve in eyes with elevated intraocular pressure (IOP). Direct quantitative evaluation of axonal transport was performed by means of the liquid scintillation counter. Our results show that topical instillation of beta-blockers, pilocarpine and epinephrine have the most positive influence on the dynamics of axonal transport in eyes with increased IOP. There was a zero or negative influence of physostigmine, neostigmine, echothiophate and partially of clonidine (isoglaucon).

Adrenergic beta-Antagonists↗
PubMed2002

Effect of ethanol on axonal transport of cholinergic enzymes in rat sciatic nerve.

The aim of this study was to investigate whether the fast axonal transport of acetylcholinesterase (AChE) and the slow transport of choline acetyltransferase (ChAT) in the sciatic nerve of the rat are affected by chronic ethanol consumption or by associated nutritional deficiency. Adult rats drank ethanol (20% [vol./vol.]) instead of water for 20 weeks. Animals that consumed an isocaloric diet, representing a nutritional deficiency, received the same amount of food as ethanol-treated rats and water with sucrose replacing ethanol isocalorically. The control group received food and water ad libitum. Axonal transport was investigated by the stop-flow ligation technique as follows. After 20 weeks, the sciatic nerve was ligated for 24 h, and accumulation of AChE and ChAT was measured above and below the ligature. No significant differences in the accumulation of both enzymes were found above the ligature. However, the accumulation of AChE transported retrogradely below the nerve ligature was reduced by 60%, but only in ethanol-treated animals. Our study results seem to indicate that, under experimental conditions, (1) neither ethanol nor associated nutritional deficiency has any effect on anterograde axonal transport of AChE and ChAT and (2) the deficit in retrograde transport of AChE is due to the direct toxic effect of ethanol and probably precedes the axonal degeneration from the most distal portions of axons toward the cell body.

Acetylcholinesterase↗
PubMed1983

Accumulation of [3H]fucose-labelled glycoproteins in the Golgi apparatus of dorsal root ganglion neurons during inhibition of fast axonal transport caused by exposure of the ganglion to Co2+-containing or Ca2+-free medium.

Previous in vitro studies have established that Co2+-containing or Ca2+-free media interfere with the initiation of the fast axonal transport of proteins. The present study has used light- and electron-microscope radioautography to compare the distribution of [3H]fucose-labelled glycoproteins in neuronal cell bodies of control dorsal root ganglia and ganglia incubated for 16-17 h in Ca2+-free medium or in medium containing 0.18 mM Co2+. The radioautographic reaction in control cell bodies was diffusely scattered throughout the cytoplasm; grain counts revealed that 22% of the reaction was associated with elements of the Golgi apparatus and 78% was over other organelles and the remainder of the cytoplasm. In most experimental cell bodies, 78% of the silver grains were clustered over elements of the Golgi complex whereas other organelles and the remainder of the cytoplasm were comparatively much less labelled; structural alterations of the Golgi apparatus were also produced by the modified media. In parallel studies where the radioactivity in nerve trunks and ganglia was measured by liquid scintillation counting, it was found that the Ca2+-free medium and the Co2+-containing medium both reduced by approximately 80% the quantity of [3H]fucose-labelled glycoproteins which were carried by the fast axonal transport system; they did so without interfering with the incorporation of [3H]fucose into glycoproteins. The results indicate that in the presence of Co2+ or in the absence of Ca2+ the proteins which are destined for fast axonal transport accumulate at the Golgi apparatus of neuronal cell bodies. These results thus suggest that Ca2+ is required for proteins to leave the Golgi region in transit to the fast axonal transport system.

Animals↗
PubMed1999

Peculiarities of axonal transport of steroid hormones (hydrocortisone, testosterone) in spinal root fibres of adult and old rats.

The labelled steroid hormones [3H]hydrocortisone and [14C]testosterone, being injected into the gray matter of the rat spinal cord L5-L6 segments, were shown to be transported at a high velocity along the ventral (anterograde) and dorsal (retrograde) root fibres. The maximum velocity of axonal transport along the ventral and dorsal roots in adult rats was, on average, 3006 +/- 101 and 3028 +/- 48 mm/day for [3H]hydrocortisone and 4594 +/- 186 and 5185 +/- 485 mm/day for [14C]testosterone, respectively. In old rats, axonal transport of steroid hormones was markedly slower. Its maximum velocity along the ventral and dorsal roots averaged to 756 +/- 64 and 738 +/- 48 mm/day for [3H]hydrocortisone and 624 +/- 54 and 608 +/- 80 mm/day for [14C]testosterone, respectively. In old rats the amount of labelled hydrocortisone incorporated into the ventral root fibres was sharply reduced (by more than an order of the value) as compared to that in adult animals. At the same time, the intensity of the labelled testosterone incorporation into the ventral root fibres did not demonstrate any significant age-related difference. The injection of low doses of steroid hormones (from less than one microgram to a few micrograms) into the lumbar spinal cord resulted in a significant hyperpolarization several hours later first of the gastrocnemius and then of deltoideus muscle fibres. In old rats, such a hyperpolarization occurred much later. It is suggested that axonal transport of steroid hormones is one of the mechanisms responsible for the effects of hormones on the tissues, which undergoes considerable changes with ageing.

Aging↗
PubMed1999

Proteolytic processing, axonal transport and differential distribution of chromogranins A and B, and secretogranin II (secretoneurin) in rat sciatic nerve and spinal cord.

The chromogranin family comprises chromogranin A and B, and secretogranin II. The present study has focused on the axonal transport of chromogranins/secretogranin II and their detailed distribution in peripheral nerves and the spinal cord. With radioimmunoassay (RIA) and column chromatography, we first studied the processing of chromogranin B and secretogranin II during axonal transport. No larger precursors of these peptides were detected in the sciatic nerves, indicating that they are already processed to a high degree early during axonal transport. We also analysed nerve segments above and below a crush, using RIA, in order to compare these accumulation data with those obtained by the cytofluorimetric-scanning (CFS) technique. For the latter technique, the amounts of accumulation distal to the crush (presumably representing recycling and retrogradely transported peptides) were 30-40% of the amounts in the proximal accumulation for chromogranin A and secretoneurin, in contrast to chromogranin B, which showed 15% recycling. With the RIA, the corresponding values for secretoneurin and PE-11 (antibody against chromogranin B) were 42% and 14%, respectively. Therefore, the data obtained by CFS were in excellent agreement with those obtained by RIA. In crushed sciatic nerves, chromogranin A was present in large axons as well as in small- and medium-sized axons. Chromogranin B was mainly restricted to large axons, while secretoneurin was localized to bundles of small axons. This differential distribution was also found in the spinal roots and in the peripheral terminals. Chromogranin A was present in both ventral and dorsal roots, and chromogranin B was detected in ventral roots and in large sensory axons in the dorsal roots. Secretoneurin was dominant in the dorsal root. Double-labelling studies with antibodies against choline acetyltransferase/vesicular acetylcholine transporter, or against tyrosine hydroxylase, confirmed that chromogranin A was distributed in cholinergic, sensory, as well as adrenergic neurons. Chromogranin B was mainly present in cholinergic motor neurons and large sensory neurons, and secretoneurin was restricted to adrenergic and sensory neurons. The present study demonstrates that chromogranins A and B, and secretoneurin are transported with fast axonal transport in the peripheral nerves, with different amounts of recycling, and that they are differentially distributed in different types of neurons in the peripheral nervous system and the spinal cord, suggesting that each of them may play a special role in subsets of neurons.

Animals↗
PubMed1988

Axonal transport of 16S acetylcholinesterase is increased in regenerating peripheral nerve in guinea-pig, but not in rat.

The axonal transport of the molecular forms of acetylcholinesterase was investigated in regenerating facial nerves of guinea-pig and rat. Four forms were separated by velocity sedimentation corresponding to 16S (A12), 10S (G4), 6S (G2) and 4S (G1) acetylcholinesterase. They displayed species-specific changes, which are in good accordance with those previously found in the neuronal perikarya. In the rat, axonal transport decreased for all forms. In the guinea-pig, however, the molecular forms showed differential changes. Whereas after transection, the nerve content of 10S acetylcholinesterase decreased, 16S activity was considerably increased. Anterograde transport of 16S acetylcholinesterase was found to be enhanced, whilst transport of the 10S from decreased. The two lighter forms showed only minor changes. Similar results were obtained for the guinea-pig sciatic nerve. Changes in the localization of acetylcholinesterase activity were investigated by electron microscopical cytochemistry. In the normal facial nerve of both species, activity was located intra-axonally in tubular membraneous structures and on the outer surface of the axonal membrane. In the regenerating facial nerve of the rat, intra-axonal as well as axolemmal activity decreased. Axonal sprouts at the end of the proximal nerve stump showed no activity. In the guinea-pig, however, activity of the axonal membrane increased. This was especially prominent on the surface of axonal sprouts. Strong activity was found also in the extracellular space between the sprouting axons and in the endoneurial space filled by collagen fibres. Biochemical analysis of this region revealed that the histochemical activity was mainly due to the A12 form. Thus it was concluded that, in the guinea-pig, axonal sprouts represent a target for axonally transported A12 acetylcholinesterase, which may also be secreted to extracellular sites.

Acetylcholinesterase↗
PubMed1997

Diabetes and axotomy-induced deficits in retrograde axonal transport of nerve growth factor correlate with decreased levels of p75LNTR protein in lumbar dorsal root ganglia.

The effect of sensory neurone axotomy on the level of retrograde axonal transport of nerve growth factor (NGF) was studied in the sciatic nerve of age-matched normal and 8-week streptozocin-diabetic rats. In normal rats a 10-day sciatic nerve crush induced a 41% decrease in transported NGF, however, axotomy of sensory neurones of diabetic rats did not significantly effect the already deficient levels of NGF undergoing retrograde transport. At first sight, this result indicated that transported NGF levels in the sciatic nerve of diabetic rats are at a residual level due to deficient availability of target-derived NGF. To confirm this, the relationship of the transported NGF to the level of sensory neurone expression of the NGF receptor proteins was analysed. Western blots of L4 and L5 dorsal root ganglia (DRG) homogenates revealed no effect of axotomy and/or diabetes on the levels of the 145-kDa tyrosine kinase form of trkA. However, the expression of p75LNTR protein in the intact DRG was reduced in diabetic compared with normal rats (56%; P < 0.01), and axotomy reduced the levels in the ipsilateral ganglia of normal but not diabetic rats - as seen for NGF axonal transport. Reductions in retrograde axonal transport of NGF in both diabetes and/or axotomy were associated with the levels of p75LNTR within the lumbar DRG.

Animals↗
PubMed1981

Importance of monovalent ions for the fast axonal transport of proteins.

Proteins labeled with [35S]methionine or [3H]leucine were generated in vitro in bullfrog dorsal root ganglia and their fast axonal transport in the spinal nerves was followed during a subsequent incubation period. Incubation of the ganglia in a medium where sucrose, choline chloride, or sodium isethionate replaced NaCl caused respectively an 88, a 37, or a 76% reduction in the quantity of proteins carried by the fast axonal transport system; no decrease in synthesis of labeled proteins was observed and protein transport followed the usual time course. Incubation of desheathed spinal nerves in a medium where sucrose replaced NaCl reduced by 67% the quantity of labeled proteins which were transported past the desheathed region. Although both the axons and the dorsal root ganglia exhibit the requirement for monovalent ions to maintain fast axonal transport, the possibility that the ionic requirements of the ganglia pertain to the somal portion of the nerve cell is discussed.

Animals↗
PubMed1988

The release of axonally transported material from an in vitro amphibian sciatic nerve preparation.

The rapid axonal transport of a pulse of [35S]methionine-labelled material was used to study the release of transported material from amphibian nerve maintained in vitro. Following creation of a moving pulse of activity in a dorsal root ganglion-sciatic nerve preparation, the ganglion was removed and the nerve placed in a three-compartment tray, the section of nerve in the middle compartment containing no truncated branches (unbranched section). All three compartments were filled with a saline solution that in some studies contained nonradioactive methionine (1.0 mmol/L). Analysis of studies in which nonradioactive methionine was absent revealed that labelled material appeared in the bathing solution of the end compartments that contained truncated branches, but not in the solution of the middle (unbranched) compartment. The quantity of label released in the branched compartments was approximately 6% of that remaining in the corresponding section of nerve following an 18-20 h incubation period. However, when nonradioactive methionine was present, all compartments showed an additional activity in the bathing solution of approximately 10% of that remaining in the nerve. In another study in which a position-sensitive detector of ionizing radiation was used to monitor progress of the pulse, it was found that activity did not enter the bathing solution of a compartment prior to the pulse of activity. It is concluded that in the absence of methionine from the bathing solution, axonally transported material is released only from regions of nerve that contain severed axons; however, the presence of methionine allows transported material to be released from nerve containing intact axons. Ultrafiltration studies and thin-layer chromatography revealed the majority of material released to be of low-molecular weight (less than 30,000 daltons) and not free [35S]methionine.

Animals↗
PubMed1990

Ethanol and opiate decrease the axonal transport of substance-P like immunoreactive material in rat vagus-nerves.

Since an enhanced retrograde axonal transport of receptor-bound opiate was observed in the ligated vagus nerves of rats treated chronically with alcohol, we decided to look at the anterograde axonal transport of substance P in the same experimental conditions and, after opiate administration. From 1 day up to 24 days' treatment with alcohol, we observed a decrease in the accumulation of substance P like immunoreactive material (SPLM) in rat ligated vagus nerves. Acute administration of lofentanil, an mu opiate agonist, caused the same reduction of anterograde axonal transport of SPLM and this effect could be prevented by naloxone. When naloxone or bezitramide, an opiate agonist, was given during the alcoholization period, the preference for alcohol in a choice test was reduced or prevented suggesting that opioid peptides are probably involved in chronic alcoholism. The present results support the idea that a common denominator could exist in drug addition and in chronic alcoholism and that substance P may be directly or indirectly involved.

Analgesics↗
PubMed1986

The effect of doxorubicin on slow and fast components of the axonal transport system in rats.

The study was designed to investigate the changes in axonal transport that result from disturbances in protein synthesis. Doxorubicin, an antineoplastic drug which interferes with the function of DNA, has a selective effect on peripheral sensory nerves because of the high vascular permeability in the dorsal root ganglia. After the intravenous administration of a moderate dose (4 mg/kg) to male Wistar rats, the transport of slow component a (SCa) was found to be retarded, transport velocity being decreased by 17% (0.85 +/- 0.06 mm/day vs 1.03 +/- 0.06 mm/day in controls). The transport kinetics of the fast anterograde and retrograde components (aFC and rFC) were unchanged after the administration of a dose of 6 mg/kg, although the relative amount of aFC was decreased by 27% (3.2 +/- 0.9% vs 4.4 +/- 1.1% in controls). It is suggested that the neuronopathy induced by doxorubicin is mediated by changes in axonal transport.

Animals↗
PubMed1999

Axonal transport of ribonucleoprotein particles (vaults).

RNA was previously shown to be transported into both dendritic and axonal compartments of nerve cells, presumably involving a ribonucleoprotein particle. In order to reveal potential mechanisms of transport we investigated the axonal transport of the major vault protein of the electric ray Torpedo marmorata. This protein is the major protein component of a ribonucleoprotein particle (vault) carrying a non-translatable RNA and has a wide distribution in the animal kingdom. It is highly enriched in the cholinergic electromotor neurons and similar in size to synaptic vesicles. The axonal transport of vaults was investigated by immunofluorescence, using the anti-vault protein antibody as marker, and cytofluorimetric scanning, and was compared to that of the synaptic vesicle membrane protein SV2 and of the beta-subunit of the F1-ATPase as a marker for mitochondria. Following a crush significant axonal accumulation of SV2 proximal to the crush could first be observed after 1 h, that of mitochondria after 3 h and that of vaults after 6 h, although weekly fluorescent traces of accumulations of vault protein were observed in the confocal microscope as early as 3 h. Within the time-period investigated (up to 72 h) the accumulation of all markers increased continuously. Retrograde accumulations also occurred, and the immunofluorescence for the retrograde component, indicating recycling, was weaker than that for the anterograde component, suggesting that more than half of the vaults are degraded within the nerve terminal. High resolution immunofluorescence revealed a granular structure-in accordance with the biochemical characteristics of vaults. Of interest was the observation that the increase of vault immunoreactivity proximal to the crush accelerated with time after crushing, while that of SV2-containing particles appeared to decelerate, indicating that the crush procedure with time may have induced perikaryal alterations in the production and subsequent export to the axon of synaptic vesicles and vault protein. Our data show that ribonucleoprotein-immunoreactive particles can be actively transported within axons in situ from the soma to the nerve terminal and back. The results suggest that the transport of vaults is driven by fast axonal transport motors like the SV2-containing vesicles and mitochondria. Vaults exhibit an anterograde and a retrograde transport component, similar to that observed for the vesicular organelles carrying SV2 and for mitochondria. Although the function of vaults is still unknown studies of the axonal transport of this organelle may reveal insights into the mechanisms of cellular transport of ribonucleoprotein particles in general.

Animals↗
PubMed2004

Axonal transport versus dendritic transport.

Neurons have polarized processes for information output and input, axons, and dendrites. This polarized architecture is essential for the neuronal function. An increasing number of molecular components that mediate neuronal polarity establishment have been characterized over the past few years. The vast majority of these molecules include proteins that act in scaffolding protein complexes to sustain the polarized anchoring of molecules. In addition, more signaling and cytoskeleton-associated proteins have been proposed for establishment of polarity. It has become evident that dendritic and axonal transport of molecules depends on scaffolding/adaptor proteins that are recognized by molecular motors. Current and future research in the neuronal cell polarity will be focused on how different cargo molecules transmit their signals to the cytoskeleton and change its dynamic properties to affect the rate and direction of vesicular movement. In this review, we discuss recent evidence that scaffolding proteins can regulate motor motility and guidance by a mechanism of substrate-cytoskeletal coupling and amino acid modifications during polarized transport.

Animals↗
PubMed1983

Subunit composition specific to axonally transported tubulin.

One week after injection of L-[35S]methionine into the dorsal motor nuclei of the guinea-pig, labelled tubulin carried down the vagal nerve by the slow phase of axonal transport was analysed by one- and two-dimensional gel electrophoresis. Transported tubulin showed a much stronger labelling of the beta-subunit. Isoelectric focussing revealed that both alpha- and beta-subunits were composed of several components. Labelled tubulin was isolated from the brain by cycles of polymerisation and depolymerisation after injection of L-[35S]methionine into the lateral ventricle, for comparison with transported tubulin from the vagal nerve. In addition to the two alpha-components and three beta-components detected in both preparations, axonally transported tubulin contained an extra component (TAX) with a molecular weight corresponding to that of beta-tubulin and with the same isoelectric point as alpha-tubulin. The axon-specific component TAX co-polymerised with tubulin isolated from the brain. Upon peptide mapping by limited proteolysis, the peptide pattern generated from TAX was similar to that of the alpha-tubulin. It is concluded that the axonally transported tubulin contains a modified alpha-subunit which is not found in the bulk of brain tubulin.

Animals↗
PubMed2000

Inhibition of N-glycan processing alters axonal transport of synaptic glycoproteins in vivo.

Synaptic glycoproteins are synthesized and glycosylated in the neuronal cell body, and conveyed to terminals by fast axonal transport. We used the alpha-mannosidase inhibitor, 2-deoxymannojirimycin (dMan), to investigate the effects of disrupting N-glycan processing on the axonal trafficking of proteins in vivo. dMan significantly reduced rapid axonal transport in retinal ganglion cells to about 34% of control values 4h after metabolic labeling; at 8 h post-labeling the inhibition was reversed. 2-D gel analysis showed that dMan completely inhibited the arrival of radiolabeled L1 and NCAM at axon terminals, and resulted in the appearance of two novel proteins of 230 kDa and 155 kDa. Our results show that disruption of the N-glycosylation pathway has an immediate inhibitory effect on total axonal transport and longer lasting effects on the trafficking of specific glycoproteins to axon terminals in vivo.

1-Deoxynojirimycin↗
PubMed1975

Rapid axonal transport in trigeminal nerve of rat.

The rat trigeminal nerve was investigated as a model system for axonal transport to identifiable sensory nerve endings. Following stereotaxic injection of [3-H]proline into the ganglion, the distribution of label in protein and other extracts of ligated or unligated infraorbital nerve was measured in replicates at various time intervals from 30 min to 3 days. In unligated nerves the average maximum velocity of somatofugal protein transport was 228 mm/day. Light microscope autoradiography demonstrated rapid intraaxonal transport of radioactive material to nerve endings in molar teeth and vibrissae. The system appears suitable for investigating the fate of axonally transported material at peripheral receptors.

Animals↗