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PubMed1986

The relationship between axonal transport of protein and demyelination in the optic nerves of mice infected with Semliki Forest virus.

Fast and slow axonal transport of protein have been studied in the optic nerves of mice infected with Semliki Forest Virus (SFV) that causes patchy demyelination throughout the CNS. Intravitreal injections of [3H]proline were given at regular intervals after virus inoculation, the labelled protein in the superior colliculi was then measured after survival periods of 18 h or 10 days, for fast and slow axonal transport studies, respectively. Fast transport studies showed an enhanced amount of protein arriving at the optic nerve terminals (superior colliculus) of the SFV-infected mice prior to the onset of demyelination. In contrast, the slow transport studies showed an enhanced amount of protein at the superior colliculus of the SFV-infected mice during the demyelination period. There was no concomitant increase in labelled protein in the retina at any time after the SFV infection. It is proposed that alteration in the transport of the protein constituents other than major myelin specific components may cause disruption of myelin maintenance in SFV infection.

Animals↗
PubMed1999

Slow axonal transport of neurofilament protein in cultured neurons.

We have investigated the axonal transport of neurofilament protein in cultured neurons by constricting single axons with fine glass fibers. We observed a rapid accumulation of anterogradely and retrogradely transported membranous organelles on both sides of the constrictions and a more gradual accumulation of neurofilament protein proximal to the constrictions. Neurofilament protein accumulation was dependent on the presence of metabolic substrates and was blocked by iodoacetate, which is an inhibitor of glycolysis. These data indicate that neurofilament protein moves anterogradely in these axons by a mechanism that is directly or indirectly dependent on nucleoside triphosphates. The average transport rate was estimated to be at least 130 micrometer/h (3.1 mm/d), and approximately 90% of the accumulated neurofilament protein remained in the axon after detergent extraction, suggesting that it was present in a polymerized form. Electron microscopy demonstrated that there were an abnormally large number of neurofilament polymers proximal to the constrictions. These data suggest that the neurofilament proteins were transported either as assembled polymers or in a nonpolymeric form that assembled locally at the site of accumulation. This study represents the first demonstration of the axonal transport of neurofilament protein in cultured neurons.

Animals↗
PubMed1984

Impaired orthograde axonal transport in acute hypoglycaemia, an effect mediated via hypothermia.

The effect of hypoglycaemia (blood glucose 1 mmol/l) on the axonal transport of acetylcholinesterase activity and noradrenaline was examined in non-diabetic rats. Rats were made hypoglycaemic over a 6-h period during which acetylcholinesterase and noradrenaline accumulated proximal to a tight ligature applied to the left sciatic nerve. The hypoglycaemic rats were either kept at room temperature, when they became profoundly hypothermic, or kept in a 31 degrees C incubator to maintain body temperature as close to normal as possible. Hypoglycaemia without temperature control caused marked reductions in the accumulation of acetylcholinesterase activity and of noradrenaline proximal to the ligature. These accumulation deficits were obviated by body heating. The findings indicate that hypoglycaemia impairs fast orthograde axonal transport, but that this effect is a consequence of hypothermia rather than glucopenia.

Acetylcholinesterase↗
PubMed1985

Retrograde axonal transport of 125I-nerve growth factor in rat ileal mesenteric nerves. Effect of streptozocin diabetes.

The retrograde axonal transport of intravenously (i.v.) administered 125I-nerve growth factor (125I-NGF) was examined in mesenteric nerves innervating the small bowel of rats with streptozocin (STZ) diabetes using methods described in detail in the companion article. The accumulation of 125I-NGF distal to a ligature on the ileal mesenteric nerves of diabetic animals was 30-40% less than in control animals. The inhibition of accumulation of 125I-NGF in diabetic animals was greater at a ligature tied 2 h after i.v. administration than at a ligature tied after 14 h, which suggests that the diabetic animals may have a lag in initiation of NGF transport in the terminal axon or retardation of transport at some site along the axon. The 125I-NGF transport defect was observed as early as 3 days after the induction of diabetes, a time before the development of structural axonal lesions, and did not worsen at later times when dystrophic axonopathy is present. Both the ileal mesenteric nerves, which eventually develop dystrophic axonopathy in experimental diabetes, and the jejunal mesenteric nerves, which never develop comparable structural alterations, showed similar 125I-NGF transport deficits, suggesting that the existence of the transport abnormality does not predict the eventual development of dystrophic axonal lesions. Autoradiographic localization of 125I-NGF in the ileal mesenteric nerves of animals that had been diabetic for 11-13 mo demonstrated decreased amounts of 125I-NGF in transit in unligated paravascular nerve fascicles. There was, however, no evidence for focal retardation of transported 125I-NGF at the sites of dystrophic axonal lesions.

Animals↗
PubMed1976

Temperature-dependence of rapid axonal transport in sympathetic nerves of the rabbit.

Stop-flow techniques were used to determine how temperature affected the axonal transport of dopamine-beta-hydroxylase (DBH) activity in rabbit sciatic nerves in vitro. These nerves were cooled locally to 2 degrees C for 1.5 hr, which caused a sharp peak of DBH activity to accumulate above the cooled region. Accumulated DBH was then allowed to resume migration at various temperatures. From direct measurements of the rate of migration, we found that the axonal transport velocity of DBH was a simple exponential function of temperature between 13 degrees C and 42 degrees C. Over this range of temperatures, the results were well described by the equation: V=0.546(1.09)T, where V is velocity in mm/hr, and T is temperature in degrees centigrade. The Q10 between 13 degrees and 42 degrees C was 2.33, and an Arrhenius plot of the natural logarithm of velocity versus the reciprocal of absolute temperature yielded an apparent activation energy of 14.8 kcal. Transport virtually halted when temperature was raised to 47 degrees C, although only about half of the DBH activity disappeared during incubation at this temperature. Another transition occurred at 13 degrees C; below this temperature, velocity fell precipitously. This was not an artifact peculiar to the stop-flow system since the rate of accumulation of DBH activity proximal to a cold-block also decreased abruptly when the temperature above the block was reduced below 13 degrees C.

Animals↗
PubMed1987

Increased axonal transport in the rat optic system after systemic exposure to methylmercury: differential effects in local vs systemic exposure conditions.

Axonal transport was studied by several techniques in the optic system of adult female Long-Evans rats following systemic exposure to methylmercury in 5 mM Na2CO3. Control rats were treated with the buffer alone. Four mg Hg/kg body weight for 4-6 days, or for 12 days, induced significant changes in the rate of protein synthesis in the retinal cells and in the rate of propagation of protein-bound radioactivity along the ganglion cell axons. Axonal transport of particulate material in both groups treated with methylmercury increased to a rate of 147 mm/day compared to 93 mm/day in controls. Methylmercury was distributed evenly throughout the retinogeniculate system. No clinical neuropathy was evident in either mercury-treated group. It is proposed that the increased rates of transport may represent an adaptive compensatory response to distal axonopathy caused by methylmercury. To investigate why systemic dosing produced effects opposite to those observed with local application of MeHg, various doses of MeHg were tested in the local and systemic paradigms, including doses which yielded equal concentrations of Hg in the retina. The results indicate that the differential response between the two treatment conditions is not a function of local dose, per se. Local and systemic application produce different dose-effect curves, which do not coincide at any dose.

Animals↗
PubMed1991

Axotomy accelerates slow component b of axonal transport.

Because the integrity of an axon depends on the supply of proteins synthesized in the cell body, we examined the effect of axotomy on the transport of structural proteins in rat motor axons, and the effect of altered transport on the rate of outgrowth after a subsequent testing axotomy. To examine the axonal transport of structural proteins, we labeled newly synthesized proteins with 35S-methionine 7 days after a "conditioning" lesion of the sciatic nerve, and removed the nerve 7-21 days later for SDS-PAGE. Tubulin, actin, calmodulin, and the 68-kD light neurofilament protein (NF-L) were identified by fluorography and removed for liquid scintillation counting. The fastest moving structural proteins were carried by slow component b (SCb) of axonal transport, which advanced 20% faster in conditioned axons: 4.2 versus 3.5 mm/day (p less than 0.01). NF-L was not accelerated, indicating that the motor for subcomponent a (SCa) of slow axonal transport was unaffected by axotomy. To measure outgrowth distances, the testing lesions was made 7 days after the conditioning lesion, and growth cones were located by the fast transport method 3 or 9 days later. The regression analysis of outgrowth distance on time showed that sprouts elongated 25% faster in conditioned axons: 4.0 versus 3.2 mm/day (p less than 0.001). These accelerated sprouts were formed too far from the spinal cord to contain SCb proteins that were synthesized after axotomy. Because the rate of outgrowth correlated closely with the rate of SCb in outgrowing sprouts (McQuarrie and Jacob, J. Comp. Neurol. 305:139-147, 1991), we conclude that SCb is accelerated throughout the length of the axon by 7 days after axotomy.

Actins↗
PubMed1998

Axonal transport of neurotrophins by visceral afferent and efferent neurons of the vagus nerve of the rat.

The receptor-mediated axonal transport of [125I]-labeled neurotrophins by afferent and efferent neurons of the vagus nerve was determined to predict the responsiveness of these neurons to neurotrophins in vivo. [125I]-labeled neurotrophins were administered to the proximal stump of the transected cervical vagus nerve of adult rats. Vagal afferent neurons retrogradely transported [125I]neurotrophin-3 (NT-3), [125I]nerve growth factor (NGF), and [125I]neurotrophin-4 (NT-4) to perikarya in the ipsilateral nodose ganglion, and transganglionically transported [125I]NT-3, [125I]NGF, and [125I]NT-4 to the central terminal field, the nucleus tractus solitarius (NTS). Vagal afferent neurons showed minimal accumulation of [125I]brain-derived neurotrophic factor (BDNF). In contrast, efferent (parasympathetic and motor) neurons located in the dorsal motor nucleus of the vagus and nucleus ambiguus retrogradely transported [125I]BDNF, [125I]NT-3, and [125I]NT-4, but not [125I]NGF. The receptor specificity of neurotrophin transport was examined by applying [125I]-labeled neurotrophins with an excess of unlabeled neurotrophins. The retrograde transport of [125I]NT-3 to the nodose ganglion was reduced by NT-3 and by NGF, and the transport of [125I]NGF was reduced only by NGF, whereas the transport of [125I]NT-4 was significantly reduced by each of the neurotrophins. The competition profiles for the transport of NT-3 and NGF are consistent with the presence of TrkA and TrkC and the absence of TrkB in the nodose ganglion, whereas the profile for NT-4 suggests a p75 receptor-mediated transport mechanism. The transport profiles of neurotrophins by efferent vagal neurons in the dorsal motor nucleus of the vagus and nucleus ambiguus are consistent with the presence of TrkB and TrkC, but not TrkA, in these nuclei. These observations describe the unique receptor-mediated axonal transport of neurotrophins in adult vagal afferent and efferent neurons and thus serve as a template to discern the role of specific neurotrophins in the functions of these visceral sensory and motor neurons in vivo.

Animals↗
PubMed1981

Axonal transport: each major rate component reflects the movement of distinct macromolecular complexes.

The proteins of the three major rate components of axonal transport in guinea pig retinal ganglion cells were analyzed by one- and two-dimensional gel electrophoresis. Each rate component consisted of a different set of proteins that remained associated with each other during transport. This suggests that each rate component represents a distinct macromolecular complex and that these complexes may be definable organelles such as microtubules, microfilaments, and smooth endoplasmic reticulum. Thus, the transport of radiolabeled proteins in the axon reflects the movement of complete subcellular rather than the movement of individual proteins.

Animals↗
PubMed1978

The effect of biogenic monomines on rapid axonal transport in the rabbit optic nerve.

Since L-dopa and serotonin have been reported to increase the rate of axonal transport in rat sciatic nerve, we decided to study the effect of these monoamines on rapid orthograde transport in the rattit optic nerve. To do this, tritiated leucine was injected into the vitreous of both eyes of 56 albino rabbits, and arrival of radioactive labeled proteins at the superior colliculus was measured at various intervals by liquid scintillation counting. Rabbits were studied 24 hr after intraperitoneal injections of (1) Sinemet + L-dopa, (2) Sinemet + 5-hydroxytryptophan, or (3) pargyline. There were 14 rabbits in each group compared to 14 controls that received no monoamies. In the monoamine-treated groups, transported labeled proteins arrived at the superior colliculus earlier, and an increased amount of radioactivity accumulated during the next several hours. The maximum amount of radioactive proteins accumulating in drug-treated animals did not differ significantly from the maximum amount in control animals. As judged by autoradiographic densitometry, retinal ganglion cell synthesis was similar in control and drug-treated animals. We suspect that the rate of rapid axonal transport is increased by monoamines, although an increased rate of ganglion cell protein synthesis is another possibility.

5-Hydroxytryptophan↗
PubMed1983

Axonal transport of acetylcholinesterase in the diabetic mutant mouse.

During the development of diabetic neuropathy in the mouse C57BL/Ks (db/db), the axonal transport of AChE molecular forms was tested in the sciatic nerve, by measuring the accumulation of enzyme activity in front of a nerve transection. No alteration of the fast flow rate of G4 and A12 molecular forms was found until 220 days of age. On the other hand, a reduced flow rate of G1 and G2 molecular forms, probably conveyed by slow axoplasmic flow, was noticed in the late phase of diabetic neuropathy. This result is consistent with the view that axonal dwindling could be related to disturbances of slow axonal transport and that the reduction in conduction velocity, observed at an earlier stage, may be due to other causes.

Acetylcholinesterase↗
PubMed1987

Treatment with an aldose reductase inhibitor can reduce the susceptibility of fast axonal transport following nerve compression in the streptozotocin-diabetic rat.

The effect of treatment with an aldose reductase inhibitor on the susceptibility of peripheral nerves to compression was studied in rats made diabetic by the injection of streptozotocin (50 mg.kg-1). The response to nerve compression was determined in untreated diabetic rats after 22 days of diabetes and compared with the response in two similar groups of diabetic rats which had been treated with the aldose reductase inhibitor 'Statil' (ICI 128436; 25 mg.kg-1.day-1 orally) either from the induction of diabetes or for 7 days prior to nerve compression. Two groups of non-diabetic rats were treated with 'Statil' for either 22 days or 7 days to act as controls. Inhibition of fast axonally transported proteins was induced by local compression of the sciatic nerves 4 h after application of 3H-leucine to the motor neurone cell bodies in the spinal cord. The inhibition of fast axonal transport was quantified by calculation of a transport block ratio. Compression at 30 mmHg for 3 h induced a significantly greater (p less than 0.05) inhibition of axonal transport at the site of compression in nerves of untreated diabetic rats (transport block ratio 0.96 +/- 0.24, n = 8) than in nerves of control rats treated with the aldose reductase inhibitor for either the shorter time of 7 days (0.71 +/- 0.17, n = 10) or the longer time of 22 days (0.69 +/- 0.08, n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Aldehyde Reductase↗
PubMed1991

Toxic neurofilamentous axonopathies and fast anterograde axonal transport. III. Recovery from single injections and multiple dosing effects of acrylamide and 2,5-hexanedione.

Fast anterograde axonal transport has been advanced as a potential site of action of acrylamide (ACR) and the neurotoxic gamma-diketones in producing nerve degeneration. The segmental analysis method of axonal transport was used to measure the rate and quantity of protein transport in the rat sciatic nerve from 1 to 24 hr after a single injection of 50 mg/kg (0.7 mmol/kg) ACR or 4 mmol/kg 2,5-hexanedione (2,5-HD). The single injection of ACR or 2,5-HD resulted in an immediate reduction in transport quantity of 48 and 43%, respectively. Transport remained depressed for 16 hr; recovery occurred from 16 to 24 hr reaching control levels at 24 hr postinjection for both toxicants. Protein transport, measured immediately after the 2nd, 4th, 7th, and 10th injections, was reduced 36-38% by 50 mg/kg ACR and 30-43% by 4 mmol/kg 2,5-HD. Therefore, both ACR and 2,5-HD produce a transient and repeated compromise of fast anterograde transport during the dosing regimen which results in distal nerve degeneration. Assuming a rate of recovery after each subsequent dose similar to the first, the protein delivery to the axon was calculated to be reduced 29% by ACR and 22% by 2,5-HD. Current evidence supports the hypothesis that a toxicant-induced reduction in protein delivery to the axon by ACR and 2,5-HD contributes to development of axonal degeneration.

Acrylamide↗
PubMed1976

The dynamics and location of axonal transport blockade by acute intraocular pressure elevation in primate optic nerve.

Axonal transport in primate optic nerve axons was studied by autoradiography, scintillation counting, and electron microscopy under conditions of short-term intraocular pressure elevation. With elevation of intraocular pressure to 30 mm. Hg below mean arterial blood pressure, blockage of transport was detected within 2 hours by autoradiography and within 1 hour by electron microscopy. The earliest buildup of radioactively labeled protein and ultrastructurally visible cellular organelles was within the scleral lamina cribrosa. The degree of blockage, judged by amount of label buildup, increased with time. Some transported material traversed the lamina cribrosa despite pressure elevation at the level tested. Reversal of transport blockade occurred rapidly after normalization of intraocular pressure.

Acute Disease↗
PubMed1985

Fast orthograde axonal transport in sciatic motoneurones and nerve temperature in streptozotocin-diabetic rats.

This study measured the velocity of fast orthograde axonal transport of incorporated 3H-proline in motoneurones of the sciatic nerve in control rats and in rats with streptozotocin-induced diabetes of 3 weeks duration. Sciatic nerve and abdominal cavity temperatures were monitored throughout the period of measurement of transport velocity, and the rats were warmed to minimise hypothermia at both sites. There was marked abdominal and sciatic nerve hypothermia immediately after operation, and this effect was more intense in diabetic rats than in control rats. In steady state, abdominal cavity temperature (mean +/- SEM) was 38.1 +/- 0.1 degree C in both control and diabetic rats, and the sciatic nerve temperatures were 37.8 +/- 0.1 degree C in controls and 37.1 +/- 0.3 degrees C in diabetic rats. The difference was not statistically significant. The velocities of orthograde axonal transport for the fastest molecules containing 3H-proline were 14.0 +/- 0.9 (SEM)mm/h for controls and 13.9 +/- 1.1 (SEM)mm/h for diabetic rats. Thus, no velocity difference was observed. The findings are discussed in relation to measurements of fast orthograde transport velocity in experimental diabetes in other studies. It is suggested that, where velocity deficits have been seen in diabetic rats, nerve hypothermia should be considered as a contributory factor.

Anesthesia↗
PubMed1998

Topical axonal transport blocker vincristine prevents nerve injury-induced spinal neuron sensitization in rats.

The effect of vincristine (Vin, a fast axonal transport blocker) to prevent any alteration in the excitability of dorsal horn neurons, following peripheral nerve injury, was investigated on 31 rats: 20 with chronic constriction injury (CCI) of the sciatic nerve and 11 sham preparations. In 15 of the 20 CCI rats, a small piece of gelfoam soaked with Vin was applied to the sciatic nerve before ligation (Vin+); in the remaining 5 rats the nerve was ligated without Vin (Vin-). The 11 sham rats were 7 Vin+ and 4 Vin-. The dorsal horn neuronal activity was recorded after 2-3 postoperative (PO) weeks. In the CCI Vin- rats, the neurons showed increased spontaneous activity and hyperresponsiveness to noxious stimulus with prolonged afterdischarges, events considered to signal central neuron sensitization. In the CCI Vin+ rats, the neuronal spontaneous and stimulated activity values were significantly lower (p < 0.001) than in the CCI Vin- rats being comparable to normal values. In sham Vin+ and Vin- rats, the neuronal activities had normal values. Given the crucial role attributed to central neuron sensitization for the development of neuropathic pain, the possibility that vincristine, by blocking the axonal transport, exerts a preventive action on this syndrome is discussed.

Action Potentials↗
PubMed2003

BPAG1n4 is essential for retrograde axonal transport in sensory neurons.

Disruption of the BPAG1 (bullous pemphigoid antigen 1) gene results in progressive deterioration in motor function and devastating sensory neurodegeneration in the null mice. We have previously demonstrated that BPAG1n1 and BPAG1n3 play important roles in organizing cytoskeletal networks in vivo. Here, we characterize functions of a novel BPAG1 neuronal isoform, BPAG1n4. Results obtained from yeast two-hybrid screening, blot overlay binding assays, and coimmunoprecipitations demonstrate that BPAG1n4 interacts directly with dynactin p150Glued through its unique ezrin/radixin/moesin domain. Studies using double immunofluorescent microscopy and ultrastructural analysis reveal physiological colocalization of BPAG1n4 with dynactin/dynein. Disruption of the interaction between BPAG1n4 and dynactin results in severe defects in retrograde axonal transport. We conclude that BPAG1n4 plays an essential role in retrograde axonal transport in sensory neurons. These findings might advance our understanding of pathogenesis of axonal degeneration and neuronal death.

Animals↗
PubMed1985

Rapid axonal transport of three molecular forms of acetylcholinesterase in the frog sciatic nerve.

Acetylcholinesterase occurs in the frog sciatic nerve under five stable molecular forms with distinct sedimentation coefficients in sucrose gradients: 3 globular forms (3.6S, 6S and 10.5S) and two asymmetric ones (14S and 18S). Whereas in birds and mammals, the asymmetric tailed forms of acetylcholinesterase are present in trace amounts in peripheral nerves and account for only a small part of the enzyme activity submitted to a rapid axonal transport, the two asymmetric 14S and 18S forms represent nearly 50% of total activity in the frog sciatic nerve and account for 60-70% of the acetylcholinesterase activity accumulated at both sides of a nerve transection, the rest being due to an accumulation of globular molecules. We showed that the three forms, 10.5S, 14S and 18S, are all carried with the fast phase of axonal transport at a velocity of 100-120 mm/day in the anterograde direction and 20-30 mm/day in the retrograde direction. The velocity of transport for the light molecular forms 3.6S and 6S could not be calculated. In addition, we observed that large amounts not only of the 10.5S but also of the asymmetric 14S and 18S forms appear to be stationary along the frog sciatic nerve, contrary to the situation described for peripheral nerves in birds or mammals. Our results thus reveal that some axonal transport parameters for the asymmetric forms of acetylcholinesterase greatly differ in the peripheral nerves of amphibians on the one hand and of birds and mammals on the other, suggesting that these heavy molecular forms might have distinct functions in the nerves of lower and higher vertebrates.

Acetylcholinesterase↗