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PubMed1998

Up-regulation of fast-axonally transported proteins in retinal ganglion cells of adult rats with optic-peroneal nerve grafts.

Metabolic labeling and quantitative 2D gel fluorography were used to assess changes in the synthesis and transport of five fast-axonally transported and developmentally regulated proteins (GAP-43, SNAP-25, and proteins of 18, 22, and 23/24 kDa) after grafting of a peroneal nerve segment onto a transected optic nerve in adult rats. After optic nerve transection alone, only GAP-43 was up-regulated significantly compared to normal adult controls. The other proteins showed little change or were down-regulated following axotomy. By 4 weeks following optic nerve transection and peroneal nerve grafting, however, GAP-43, proteins 22 and 23/24 kDa showed a sustained up-regulation in synthesis and transport compared to normal controls; SNAP-25 and protein 18 kDa showed levels of expression similar to or slightly greater than normal controls. Increased expression of GAP-43 in retinal ganglion cells was also examined with immunocytochemistry. While a transient up-regulation of GAP-43 in retinal ganglion cells was observed following optic nerve transection, a sustained increase in GAP-43 immunoreactivity was present only in animals with nerve grafts. Backfilling of retinal ganglion cells from the grafts with horseradish peroxidase combined with GAP-43 immunocytochemistry revealed that all retinal ganglion cells with axons growing into the grafts were positive for GAP-43, but not all retinal ganglion cells showing GAP-43 immunoreactivity were extending axons into the grafts. We conclude that the presence of a nerve graft sustains the up-regulation of a number of proteins including GAP-43, and that this up-regulation is correlated with an increased potential for nerve growth, but other as yet unknown factors or conditions appear to play a role in determining if this growth potential will be realized.

Aging↗
PubMed1991

Changes in fast axonal transport of glycoproteins in optic nerves of mice infected with Semliki Forest virus.

[3H]fucose incorporation into mouse retinae and subsequent axonal transport of glycoproteins to optic nerve terminals was studied before and during optic nerve demyelination induced by Semliki Forest virus (SFV) infection. As was previously found for [3H]proline-labelled protein, axonally transported glycoprotein was increased before demyelination. Fluorographic analysis of the increased glycoproteins and proteins, after separation by gel electrophoresis, showed particularly large increases in labelling of 2 glycoproteins (38.1 kDa and 45.0 kDa) and 3 protein (15.9 kDa, 23.8 kDa and 27.7 kDa) bands. These increases were due to host-cell rather than viral components. At the time of demyelination, however, [3H]fucose incorporation into retinae of SFV-infected mice was significantly depressed, resulting in reduced label incorporation into axonally transported glycoproteins. Since glycoproteins play a role in axon-glia recognition and adhesion, the early changes in their axonal transport may contribute to the mechanism of demyelination.

Animals↗
PubMed1974

The polypeptide composition of intra-axonally transported proteins: evidence for four transport velocities.

Using a method of gradient gel electrophoresis coupled with autoradiography, we have analyzed the polypeptide composition of the proteins being transported down the axons of the projecting neurons of the rabbit retina. This analysis reveals: (1) the molecular weight distribution of 43 transported polypeptides; (2) the existence of at least four components of intra-axonal protein transport, each characterized by an unique polypeptide composition as well as by an unique velocity of transport; (3) the disappearance of individual labeled intra-axonally transported proteins from the axons and synaptic terminals with half-times ranging from several hours to more than 8 days. The possibility that intra-axonal transport functions as a temporal mediator of alterations in axonal or synaptic events is discussed in relation to these findings.

Animals↗
PubMed1979

Axonal transport of adrenaline, noradrenaline and phenylethanolamine-N-methyl transferase (PNMT) in sympathetic neurons of the cod, Gadus morhua.

The axonal transport of adrenaline, noradrenaline and phenylethanolamine-N-methyl transferase (PNMT) has been studied in vivo in sympathetic neurons of the splanchnic nerve in the cod, Gadus morhua. Adrenaline and noradrenaline are transported at a mean axonal transport rate of 16 mm/day. After correction for a non-mobile fraction of adrenaline and noradrenaline, which does not contribute to the amine accumulation proximal to a ligature, a maximal rate of transport was calculated to about 45 mm/day for both amines. The increased level of catecholamines in front of a ligature could be depleted by reserpine treatment, which strongly suggests that both amines are stored in granules. PNMT is transported at a slow rate of 2 mm/day. The subcellular distribution of the cod PNMT was exclusively non-particular. The cod PNMT was further characterized by studying substrate specificity, temperature and pH optima. It is concluded that adrenaline and noradrenaline, stored in granules, are transported in a proximo-distal direction at a high rate compared to PNMT.

Animals↗
PubMed1985

Orthograde axonal transport of optic nerve and injury--morphological study.

To investigate the effects of injury to the orthograde axonal transport in the optic nerve, horseradish peroxidase (HRP) was injected into the vitreous of the cat eye after various types of optic nerve injury, and the retina and optic nerve were examined with light and electron microscopes 8 hours after the injection. The optic nerve was sectioned in one eye at about 6 mm behind the eyeball and the optic nerve of the contralateral eye was used as the control. HRP reaction products were frequently observed within the retinal ganglion cells and their axons of the nerve fiber layer as well as in the retrolaminar optic nerve on the experimental side, and the findings were similar to those on the control side. The optic nerve was injured by cryocoagulation for 10 seconds or 30 seconds, and ischemic changes of various degrees were induced. Intracellular and intra-axonal HRP reaction products were markedly reduced at the retrolaminar portion, and the degree of reduction depended on the duration of cryocoagulation. The section of the optic nerve had, at least in the early stage, only minimal effects on the orthograde axonal transport, but the optic nerve injury accompanied by ischemic changes markedly blocked the axonal transport in both the inner part of the retina and the optic nerve.

Animals↗
PubMed1993

Axonal transport of dopamine-containing vesicles labelled in vivo with [3H]reserpine.

Axonal transport of the vesicular monoamine transporter was assayed in the rat brain by in vivo binding of the specific ligand [3H]reserpine. Because of the marked localization of reserpine binding sites in dopaminergic cell bodies and nerve terminals, the dopaminergic nigrostriatal pathway was chosen for the study of the axonal transport of the monoamine carrier present in the membrane of synaptic vesicles. When labelled reserpine was injected into the substantia nigra, a delayed accumulation of radioactivity in the ipsilateral striatum was observed approximately 4 h after the injection. Similarly, injection into the right striatum was followed by a substantial accumulation of radioactivity in the ipsilateral substantia nigra, which was prevented by peripheral injection of unlabelled reserpine or tetrabenazine. This process was rapid and dependent on microtubules. In senescent rats, the amount of retrogradely transported [3H]reserpine was significantly reduced. These results demonstrate that labelled reserpine may be used to monitor in vivo fast axonal transport in central neurons.

Aging↗
PubMed1982

Position-sensitive detector studies of the axonal transport of a pulse of radioisotope.

Axonal transport of a pulse of 35S-methionine-labelled material was studied in vitro in amphibian sciatic nerve using position sensitive detectors. Following formation of a pulse of activity using the cold block technique, the nerve was ligated proximal and distal to the pulse and its movement monitored at room temperature (22.5-23.5 degrees C) for up to 16 h. Material transported in the anterograde direction did so with an average maximum velocity of 147 mm/d. The pulse was found to disperse at an average rate of 0.23 mm/mm travel; however, dispersion was found to vary from preparation to preparation more than would be predicted from experimental error alone. Label was observed to reverse direction at the distal ligature in only 2 of 13 preparations. Reversal of label began within approximately 0.4 h of first arrival, and the most rapidly retrogradely transported material moved at a velocity of 80% that of the most rapidly anterogradely transported material.

Animals↗
PubMed1989

Effects of p-xylene inhalation on axonal transport in the rat retinal ganglion cells.

Although the solvent xylene is suspected of producing nervous system dysfunction in animals and humans, little is known regarding the neurochemical consequences of xylene inhalation. The intent of this study was to determine the effect of intermittent, acute, and subchronic p-xylene exposure on the axonal transport of proteins and glycoproteins within the rat retinofugal tract. A number of different exposure regimens were tested ranging from 50 ppm for a single 6-hr exposure to 1600 ppm 6 hr/day, 5 days/week, for a total of 8 exposure days. Immediately following removal from the inhalation chambers rats were injected intraocularly with [35S]methionine and [3H]fucose (to label retinal proteins and glycoproteins, respectively) and the axonal transport of labeled macromolecules to axons (optic nerve and optic tract) and nerve endings (lateral geniculate body and superior colliculus) was examined 20 hr after precursor injection. Only relatively severe exposure regimens (i.e., 800 or 1600 ppm 6 hr/day, 5 days/week, for 1.5 weeks) produced significant reductions in axonal transport; there was a moderate reduction in the axonal transport of 35S-labeled proteins in the 800-ppm-treated group which was more widespread in the 1600 ppm-treated group. Transport of 3H-labeled glycoproteins was less affected. Assessment of retinal metabolism immediately after isotope injection indicated that the rate of precursor uptake was not reduced in either treatment group. Furthermore, rapid transport was still substantially reduced in animals exposed to 1600 ppm p-xylene and allowed a 13-day withdrawal period. These data indicate that p-xylene inhalation decreases rapid axonal transport supplied to the projections of the rat retinal ganglion cells immediately after cessation of inhalation exposure and that this decreased transport is still apparent 13 days after the last exposure. This decreased supply of cellular materials to the axon and nerve ending regions could initiate the neuronal malfunction reported in solvent-exposed animals and humans.

Administration, Inhalation↗
PubMed1980

Batrachotoxin blocks slow and retrograde axonal transport in vivo.

The accumulation of choline acetyltransferase (CAT) proximal to and nerve growth factor (NGF) distal to the intraneural site of tetrodotoxin (TTX) or batrachotoxin (BTX) injection in vivo was used to monitor orthograde and retrograde axonal transport. Orthograde axonal transport was blocked by BTX for up to 7-10 days while TTX had no effect. Similarly, retrograde transport of [125I]NGF was blocked by BTX and not by TTX.

Afferent Pathways↗
PubMed2005

A mutation in dynein rescues axonal transport defects and extends the life span of ALS mice.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterized by motoneuron degeneration and muscle paralysis. Although the precise pathogenesis of ALS remains unclear, mutations in Cu/Zn superoxide dismutase (SOD1) account for approximately 20-25% of familial ALS cases, and transgenic mice overexpressing human mutant SOD1 develop an ALS-like phenotype. Evidence suggests that defects in axonal transport play an important role in neurodegeneration. In Legs at odd angles (Loa) mice, mutations in the motor protein dynein are associated with axonal transport defects and motoneuron degeneration. Here, we show that retrograde axonal transport defects are already present in motoneurons of SOD1(G93A) mice during embryonic development. Surprisingly, crossing SOD1(G93A) mice with Loa/+ mice delays disease progression and significantly increases life span in Loa/SOD1(G93A) mice. Moreover, there is a complete recovery in axonal transport deficits in motoneurons of these mice, which may be responsible for the amelioration of disease. We propose that impaired axonal transport is a prime cause of neuronal death in neurodegenerative disorders such as ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2003

Effects of extracellular atp on axonal transport in cultured mouse dorsal root ganglion neurons.

In primary sensory neurons, extracellular ATP plays important roles in nociception and afferent neurotransmission. Here we investigated the effects of ATP on axonal transport in cultured adult mouse dorsal root ganglion neurons using video-enhanced microscopy. Continuous application (26 min) of ATP (100 microM) significantly increased axonal transport of membrane-bound organelles in anterograde and retrograde directions. All neurons tested (n=5) responded to ATP. The number of transported organelles per min began to increase within 2 min and peaked at 11-14 min after the start of ATP application, and thereafter gradually declined. The peak values in both directions were approximately 140% of the initial values before application. The P2 receptor antagonist suramin (1 mM) completely blocked the effect of ATP. Uridine 5'-triphosphate (UTP; 100 microM) produced a similar effect to ATP, with peak values at 11 min reaching 140% in both directions (n=6). ADP (100 microM; n=5), alpha,beta-methylene ATP (100 microM; n=6), or 2-methylthio ATP (100 microM; n=5) had no effect on axonal transport. Our findings indicate that extracellular ATP is able to increase axonal transport in primary sensory neurons. The equal potency of ATP and UTP with no detectable response to ADP, alpha,beta-methylene ATP, or 2-methylthio ATP suggests the possible involvement of P2Y(2) receptors. Extracellular ATP may play an important role in the modulation of axonal transport in sensory neurons.

Adenosine Diphosphate↗
PubMed1981

Nerve-specific enolase and creatine phosphokinase in axonal transport: soluble proteins and the axoplasmic matrix.

The axonal transport of two soluble enzymes of intermediary metabolism was evaluated: the nerve-specific form of the glycolytic enzyme enolase (NSE) and the brain isozyme of creatine phosphokinase (CPK). Previously, little was known about the intracellular movements of the soluble proteins of the cell. Although the soluble enzymes of glycolysis and other pathways of intermediary metabolism have been thought to be freely diffusing in the cytosol, many are required in the axonal extremities of the neuron and must be transported to the sites of utilization. Comigration of purified enzymes with radioactive polypeptides associated with specific rate components of axonal transport in two-dimensional gel electrophoresis indicates that both NSE and CPK move in the axon solely as part of the group of proteins known as slow component b (SCb) at a rate of 2 mm/day. Peptide mapping following limited proteolysis confirmed identification of NSE and CPK in SCb. Materials associated with SCb have been shown to move coherently along the axon and to behave as a discrete cellular structure, the axoplasmic matrix. Association of two soluble enzymes, NSE and CPK, with the SCb complex of proteins requires a reevaluation of the assumption that these and other soluble proteins of the axon are freely diffusible.

Animals↗
PubMed1981

Axonal transport of enzymes and labeled proteins in experimental axonopathy induced by p-bromophenylacetylurea.

Axonal transport was studied by several techniques in the sciatic nerves of adult male Sprague-Dawley rats with neuropathy induced by treatment with p-bromophenylacetylurea (BPAU) in dimethylsulfoxide solution. Control rats were treated with solvent alone. BPAU, 200 mg/kg, induced severe muscle weakness in the hindlimbs, beginning after a latent period of 1 week and progressing to near total paralysis by 2 weeks. Axonal transport of the endogenous transmitter enzymes, acetylcholinesterase, dopamine-beta-hydroxylase and choline acetyltransferase, was normal at both 2 and 15 days after administration of BPAU, as judged by the accumulation of enzyme activity above and below a set of double ligatures on the sciatic nerve. The velocity of fast anterograde transport of [35S] methionine labeled protein was also unaffected by BPAU. However, 4 abnormalities of transport were detected in BPAU- treated rats: (1) doubling of the time for initiation of fast anterograde transport after precursor injection in the dorsal root ganglion, (2) 25% fall in the velocity of slow axonal transport of [3H] leucine labeled protein, (3) 30% reduction in the proximal accumulation of fast transported labeled protein in ligated nerve, 8-30 h after injection of precursor, and (4) 50-60% reduction in distal accumulation of "early arriving" labeled protein, 8-14 h after precursor injection. The last abnormality, suggesting an impaired turnaround from anterograde to retrograde transport, was detected as soon as 2 days after BPAU administration. The turnaround abnormality was correlated with the severity of neuropathy as estimated by independent clinical scoring in the group of rats treated with 200 mg/kg of drug. However, further studies showed that turnaround was delayed even in rats treated with doses as low as 50 mg/kg, which never led to clinically evident neuropathy. Nevertheless it is proposed that the abnormalities of transport play a role, as yet undefined, in the distal axonopathy caused by BPAU.

Acetylcholinesterase↗
PubMed1983

Velocity of axonal transport of phospholipid in rat sciatic nerve.

The difficulties involved in measuring axonal transport velocity for phospholipid in mammalian axons have been overcome by using a reversible local cold-block technique which causes a local accumulation of labeled phospholipid in rat sciatic nerve that follows injection of [methyl 3H]choline chloride into the L5 dorsal root ganglion. On rewarming the nerve a distinct front of [3H]-activity moves distally from the cold-block site at 17.8 mm X h-1, a velocity not significantly different from that previously determined for protein. This observation provides further support for the hypothesis that fast axonal transport conveys membranes assembled in the cell body.

Animals↗
PubMed1987

Slow axonal transport in experimental hypoxia and in neuropathy induced by p-bromophenylacetylurea.

The slow axonal transport of proteins radiolabeled by incorporation of [35S]methionine was studied in motor nerves of rats subjected to chronic hypoxia. The conditions involved exposure to an atmosphere of 8-10% oxygen for periods of 3, 5, or 10 weeks. An experimentally verified computer model predicted a drop in mean endoneurial oxygen tension from 30.5 to 19 mm Hg, despite a measured increase in circulating hemoglobin from 16 to 22 g%. Nerve conduction velocity was unaffected during the early stages of hypoxia. After 10 weeks of hypoxia, conduction velocity still appeared normal in the sciatic nerve but was reduced in the caudal nerve by 2.5-4.5 m/s. At no time, however, was there evidence of impaired slow axonal transport, which proceeded with a mean velocity between 1 and 2 mm/day. Another set of experiments was performed to evaluate slow axonal transport in motor nerves of rats with peripheral neuropathy induced by the toxicant, p-bromophenylacetylurea. The results suggested a lower transport velocity in rats showing total hind-limb paralysis as compared with rats showing only mild to moderate motor dysfunction. The difference, however, could have reflected accelerated transport in mild neuropathy. In our view, the observations in experimental hypoxia- and toxicant-induced neuropathy are noteworthy for the resistance of slow transport to perturbation of the neuronal environment.

Animals↗