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PubMed2002

Gene replacement in mice reveals that the heavily phosphorylated tail of neurofilament heavy subunit does not affect axonal caliber or the transit of cargoes in slow axonal transport.

The COOH-terminal tail of mammalian neurofilament heavy subunit (NF-H), the largest neurofilament subunit, contains 44-51 lysine-serine-proline repeats that are nearly stoichiometrically phosphorylated after assembly into neurofilaments in axons. Phosphorylation of these repeats has been implicated in promotion of radial growth of axons, control of nearest neighbor distances between neurofilaments or from neurofilaments to other structural components in axons, and as a determinant of slow axonal transport. These roles have now been tested through analysis of mice in which the NF-H gene was replaced by one deleted in the NF-H tail. Loss of the NF-H tail and all of its phosphorylation sites does not affect the number of neurofilaments, alter the ratios of the three neurofilament subunits, or affect the number of microtubules in axons. Additionally, it does not reduce interfilament spacing of most neurofilaments, the speed of action potential propagation, or mature cross-sectional areas of large motor or sensory axons, although its absence slows the speed of acquisition of normal diameters. Most surprisingly, at least in optic nerve axons, loss of the NF-H tail does not affect the rate of transport of neurofilament subunits.

Action Potentials↗
PubMed1994

A review of axonal transport of metals.

Neurons have efficient mechanisms for the transport of organelles and chemical substances in axons to the nerve terminals and back to the cell bodies. Enzymes involved in transmitter synthesis, peptide transmitters and their precursors are examples of macromolecules that are transported down the axon, anterogradely. For final degradation and possible reuse, many constituents are transported back to the cell body, retrogradely. Retrograde transport is also a pathway by which certain toxins may bypass the blood-brain barrier and accumulate in neurons. In recent years, it has been shown that certain metals may accumulate in neurons following retrograde transport. The metals for which retrograde transport has been demonstrated include lead, cadmium and mercury. In this article recent findings regarding axonal transport of metals are reviewed. The putative mechanisms involved in the uptake of metals into the nerve terminal and the fate of metals in the cell body are outlined. Axonal transport of metals as a possible etiological factor in diseases of the human nervous system is discussed.

Animals↗
PubMed1985

Subcellular storage and axonal transport of neuropeptide Y (NPY) in relation to catecholamines in the cat.

The subcellular storage of neuropeptide Y-like immunoreactivity (NPY-LI) in peripheral sympathetic neurons and adrenal gland as well as its axonal transport in the sciatic nerve was studied in relation to catecholamines in the cat. In the subcellular fractions from different parts of sympathetic neurons, i.e. cell bodies (coeliac ganglia), axons (sciatic nerve) and terminals (spleen), the NPY-LI was found together with noradrenaline (NA) in heavy fractions assumed to contain large dense-cored vesicles. In addition, minor lighter fractions in the coeliac ganglion contained NPY-LI. The molar ratio between vesicular NA and NPY was high in the terminal regions (150 to 1) and much lower in axons and cell bodies (10 to 1), thus reflecting the different mechanisms of resupply for classical transmitter and peptide. In the adrenal gland the NPY-LI was mainly located in the catecholamine-storing chromaffin-granule fraction and also to a smaller extent in lighter fractions. Using reversed-phase HPLC, one molecular form of NPY-LI corresponding to porcine NPY was found in the coeliac ganglion, while the adrenal medulla also contained minor peaks with NPY-LI in addition to the main form, which co-eluted with porcine NPY. NA was stored both in light and heavy fractions in the spleen, while it was mainly found in heavier fractions in the sciatic nerve. In the coeliac ganglion, most of the noradrenaline was present in a non-particulate form. The anterograde transport rate for NPY-LI in the sciatic nerve was estimated to be about 9 mm h-1. A minor retrograde transport of NPY-LI was also detected. In conclusion, the present data suggest that NPY, a peptide with sympathoactive actions, is co-stored with NA in heavy fractions corresponding to large dense-cored vesicles, while light fractions with small dense-cored vesicles probably contain NA but not NPY-LI. The main resupply of NPY to terminals is, in contrast to NA, most likely by axonal transport, which implicates differences in the storage, turnover and release of these co-existing substances in the sympathoadrenal system.

Adrenal Medulla↗
PubMed2002

Distribution of a lysosomal enzyme in the adult brain by axonal transport and by cells of the rostral migratory stream.

A portion of the lysosomal enzymes produced by cells is secreted, diffuses through extracellular spaces, and can be taken up by distal cells via mannose-6-phosphate receptor-mediated endocytosis. This provides the basis for treating lysosomal storage diseases, many of which affect the CNS. Normal enzyme secreted from a cluster of genetically corrected cells has been shown to reverse storage lesions in a zone of surrounding brain tissue in mouse disease models. However, low levels of enzyme activity and reduction of storage lesions also have been observed at sites in the brain that may not be explained by a contiguous gradient of secreted enzyme diffusing away from the genetically corrected cells. No direct evidence for alternative mechanisms of enzyme transport has been shown, and little is understood about the intracellular movement of lysosomal enzymes in neurons. We investigated whether axonal transport could occur, by expressing an eukaryotic lysosomal enzyme that can be visualized in tissue sections (beta-glucuronidase) in brain structures that have defined axonal connections to other structures. This resulted in the transfer of enzyme to, and a reversal of storage lesions in, neurons that project to the gene expression site, but not in nearby structures that would have been corrected if the effect had been mediated by diffusion. In addition, transduction of cells in the subventricular zone resulted in the uptake of beta-glucuronidase by cells entering the rostral migratory stream. Gene transfer to specific neuronal circuits or cells in migratory pathways may facilitate delivery to the global brain lesions found in these disorders.

Animals↗
PubMed1993

Subcellular distribution and immunological detection of retrograde axonally transported proteins in acrylamide and diabetic neuropathies.

Neuropathies produced by both acrylamide- and streptozotocin-induced diabetes in the rat are accompanied by a deficit in the retrograde axonal transport of a defined group of proteins that can be visualized on two-dimensional polyacrylamide gels. In this work, these proteins are identified as being primarily soluble and being absent from rat brain. They are not immunologically related to the major retrogradely transported protein synaptophysin. Polyclonal antiserum to the proteins was produced in mice and used to confirm the reduction in their retrograde transport in sciatic nerve of diabetic and acrylamide-treated rats.

Acrylamide↗
PubMed1977

Role of gangliosides in the uptake and retrograde axonal transport of cholera and tetanus toxin as compared to nerve growth factor and wheat germ agglutinin.

Previous investigations have shown that tetanus toxin is transported retrogradely in all peripheral neurons whereas the transport of NGF is confined to adrenergic and sensory neurons. Other macromolecules with molecular weights and general physiochemical properties similar to NGF and tetanus toxin (e.g., cytochrome C, insulin, horseradish peroxidase and bovine serum albumin) are not transported to a detectable extent if injected in comparable molar concentrations. For tetanus toxin, which is transported in all peripheral neurons, it has be assumed that it's retrograde transport depends on properties common to all neurons. In view of the relatively high ganglioside content of the neurons and the high affinity of tetanus toxin for the trisialoganglioside GT1, we studied the influence of gangliosides on the retrograde transport of tetanus toxin as compared to NGF. We included into the study cholera toxin which is known to have a high affinity for the monosialoganglioside GM1 and wheat germ agglutinatinin, a lectin with specific affinity for glycoproteins with N-acetyl-glucosamine residues. Both cholera toxin and wheat germ agglutinin were transported efficiently in all peripheral neurons. Preincubation of 125I-cholera toxin with monosialoganglioside GM1 completely blocked its retrograde axonal transport. The transport of NGF and wheat germ agglutinin was affected neither by various purified gangliosides nor by a mixture of bovine brain gangliosides. The transport of tetanus toxin was only reduced by 50% both by the trisialoganglioside GT1 and the bovine ganglioside mixture.

Adrenergic Fibers↗
PubMed1984

Inhibition of fast axonal transport by erythro-9-[3-(2-hydroxynonyl)]adenine.

erythro-9-[3-(2-Hydroxynonyl)]adenine, an inhibitor of protein carboxylmethylation and dynein-ATPase activity, inhibited fast axonal transport in vitro in frog sciatic nerves. Its site of action might be associated with an ATPase on which transport depends, since specific carboxylmethylation inhibitors lacked effects on transport. The levels of high energy phosphates and protein synthesis were unaffected by the drug at a transport-inhibiting concentration, making disturbances due to metabolic effects less likely. An erythro-9-[3-(2-hydroxynonyl)]adenine-sensitive ATPase was looked for in various nerve fractions but has so far not been resolved.

Adenine↗
PubMed1982

Axonal transport of nerve growth factor and serum albumin in the dystrophic mouse.

Specific (nerve growth factor, NGF) and non-specific (serum albumin, BSA) uptake followed by retrograde axonal transport was studied in the sciatic nerves of normal (C57BL/6J) and dystrophic (dy2J/dy2J) mice. In the dystrophic mouse there was a significant decrease in the amount of NGF transported to dorsal root ganglia or BSA accumulating at a ligature placed on the sciatic nerve.

Animals↗
PubMed1984

Assessment of possible transneuronal changes in the retina of rats with inherited retinal dystrophy: cell size, number, synapses, and axonal transport by retinal ganglion cells.

In pigmented RCS rats with inherited retinal dystrophy, most photoreceptor cells disappear between postnatal days 20 and 100. We have examined the time course of the degeneration of photoreceptor nuclei and synapses and determined whether transneuronal changes occur in the inner nuclear layer (INL), inner plexiform layer (IPL), and retinal ganglion cells following loss of photoreceptor cells in these animals. Electron microscopic photomontages of the entire thickness of the IPL of dystrophic (RCS-p+) and control (RCS-rdy+ p+) rats 334 to 515 days old were prepared, and synapses were counted and identified as either conventional (amacrine) or ribbon (bipolar) types. Neither the incidence of synapses in the IPL nor the ratio of conventional to ribbon synapses differed in the dystrophic and control retinas. Ganglion cell diameter, perimeter, area, and density were measured from drawings of wholemount preparations of dystrophic and control rats 105 days and older. Diameter, perimeter, area and number of ganglion cells were not significantly different in the two genotypes. Anterograde axonal transport was measured by studying the displacement of labeled material as it traveled along ganglion cell axons and accumulated in the superior colliculus. The normal and dystrophic rats showed no significant difference in (1) the rates of rapidly moving components (approximately 110-180 mm/day) and slowly moving components (1.7-2.5 mm/day) or (2) the amount of radioactive material transported to the superior colliculus. The absence of transneuronal changes in retinal ganglion cells of RCS rats contrasts with results obtained earlier in rd mice (Graftstein et al., '72). Unlike the RCS rat, retinal degeneration in rd mice occurs before the maturation of the retina. We hypothesize that the ganglion cells may be more affected by loss of input early in development, and, therefore, ganglion cells of retinal dystrophic rats are less affected despite little or no synaptic input for several months. Furthermore, any reduction in the electrical activity of retinal ganglion cells that might follow loss of photoreceptor cells does not result in a significantly decreased rate of axonal transport.

Aging↗
PubMed1990

Synthesis, axonal transport, and turnover of the high molecular weight microtubule-associated protein MAP 1A in mouse retinal ganglion cells: tubulin and MAP 1A display distinct transport kinetics.

Microtubule-associated proteins (MAPs) in neurons establish functional associations with microtubules, sometimes at considerable distances from their site of synthesis. In this study we identified MAP 1A in mouse retinal ganglion cells and characterized for the first time its in vivo dynamics in relation to axonally transported tubulin. A soluble 340-kD polypeptide was strongly radiolabeled in ganglion cells after intravitreal injection of [35S]methionine or [3H]proline. This polypeptide was identified as MAP 1A on the basis of its co-migration on SDS gels with MAP 1A from brain microtubules; its co-assembly with microtubules in the presence of taxol or during cycles of assembly-disassembly; and its cross-reaction with well-characterized antibodies against MAP 1A in immunoblotting and immunoprecipitation assays. Glial cells of the optic nerve synthesized considerably less MAP 1A than neurons. The axoplasmic transport of MAP 1A differed from that of tubulin. Using two separate methods, we observed that MAP 1A advanced along optic axons at a rate of 1.0-1.2 mm/d, a rate typical of the Group IV (SCb) phase of transport, while tubulin moved 0.1-0.2 mm/d, a group V (SCa) transport rate. At least 13% of the newly synthesized MAP 1A entering optic axons was incorporated uniformly along axons into stationary axonal structures. The half-residence time of stationary MAP 1A in axons (55-60 d) was 4.6 times longer than that of MAP 1A moving in Group IV, indicating that at least 44% of the total MAP 1A in axons is stationary. These results demonstrate that cytoskeletal proteins that become functionally associated with each other in axons may be delivered to these sites at different transport rates. Stable associations between axonal constituents moving at different velocities could develop when these elements leave the transport vector and incorporate into the stationary cytoskeleton.

Animals↗
PubMed1986

Slow component-a of axonal transport, nerve myo-inositol, and aldose reductase inhibition in streptozocin-diabetic rats.

This study measured sugars and polyols, weight/unit length, and slow component-a of axonal transport (SCa) in dorsal root afferents of the sciatic nerves of control rats and rats with streptozocin (STZ)-induced diabetes of 4-wk duration. The effects of two treatments--aldose reductase inhibition [Statil ("Statil" is a trademark; the property of Imperial Chemical Industries PLC.) ICI 128436 at 25 mg/kg/day, p.o.] and myo-inositol supplementation (650 mg/kg/day, p.o.)--were studied in control and diabetic groups. Inclusion of untreated controls and diabetics gave a total of six groups for the study. The treatments were begun on the day after injection of STZ and were maintained throughout the protocol. The sciatic nerves of the diabetic (untreated) rats showed accumulation of sorbitol and fructose, depletion of myo-inositol, and an 8% increase in weight/unit length. All of these abnormalities were prevented by treatment with Statil. Treatment of diabetic rats with myo-inositol prevented its depletion in the sciatic nerve, but did not affect the accumulation of sorbitol and fructose nor the increase in weight/unit length. Neither treatment exerted any apparent effect on body weight, blood glucose, nerve weight, or nerve sugars and polyols in the control rats. The diabetic rats showed a retardation of the wave of transported-labeled protein (shown as increased leftward skewness of the wave) and a reduction in mean transport velocity (calculated as the mean velocity for all segments contributing to the transport wave: 0.96 +/- 0.09 mm/day in diabetics versus 1.15 +/- 0.07 mm/day in controls).(ABSTRACT TRUNCATED AT 250 WORDS)

Aldehyde Reductase↗
PubMed1984

An anterograde neuroanatomical tracing method that shows the detailed morphology of neurons, their axons and terminals: immunohistochemical localization of an axonally transported plant lectin, Phaseolus vulgaris leucoagglutinin (PHA-L).

A new neuroanatomical method for tracing connections in the central nervous system based on the anterograde axonal transport of the kidney bean lectin, Phaseolus vulgaris-leucoagglutinin (PHA-L) is described. The method, for which a detailed protocol is presented, offers several advantages over present techniques. First, when the lectin is delivered iontophoretically, PHA-L injection sites as small as 50-200 micron in diameter can be produced, and are clearly demarcated since the neurons within the labeled zone are completely filled. Second, many morphological features of such filled neurons are clearly demonstrated including their cell bodies, axons, dendritic arbors and even dendritic spines. Third, there is some evidence to suggest that only the neurons at the injection site that are filled transport demonstrable amounts of the tracer, raising the possibility that the effective injection site can be defined quite precisely. Fourth, even with the most restricted injections, the morphology of the labeled axons and axon terminals is clearly demonstrated; this includes boutons en passant, fine collateral branches, and various terminal specializations, all of which can be visualized as well as in the best rapid Golgi preparations. Fifth, when introduced iontophoretically, PHA-L appears to be transported preferentially in the anterograde direction; only rarely is it transported retrogradely. Sixth, PHA-L does not appear to be taken up and transported effectively by fibers of passage. Seventh, there is no discernible degradation of the transported PHA-L with survival times of up to 17 days. Finally, since the transported marker can be demonstrated with either peroxidase or fluorescent antibody techniques, it may be used in conjunction with other neuroanatomical methods. For example, double anterograde labeling experiments can be done using the autoradiographic method along with immunoperoxidase localization of PHA-L, and the retrogradely transported fluorescent dyes can be visualized in the same tissue sections as PHA-L localized with immunofluorescence techniques.

Animals↗
PubMed1978

A sensitive method for histochemical demonstration of horseradish peroxidase in neurons following retrograde axonal transport.

A study was made on the effects of various fixatives and some other histochemical parameters used in the procedure for demonstrating labeled neurons following retrograde axonal transport of horseradish peroxidase (HRP). The enzyme was injected into the tongue of adult mice and the results were obtained by counting labeled hypoglossal neurons following certain variations in the procedure. Paraformaldehyde in the fixative should be avoided since it reduces the number of labeled neurons as compared to glutaraldehyde in a concentration of 1.5-2.5% Fixation for about 4 h is recommended followed by a wash in 5% sucrose buffer overnight. Variables in the histochemical procedure were systematically studied in order to determine optimal pH, buffer type, buffer concentration and substrate concentration. The effect of using a "preincubation" in buffer containing only diaminobenzidine tetrahydrochloride (DAB) was also examined. These results were used to develop a modified histochemical procedure which produced a substantial increase in the number of detectable HRP-labeled neurons as compared to equivalent sections that were reacted in the incubation medium described by Graham and Karnovsky. The modified histochemical procedure involves incubation (no preincubation with DAB only) of sections in the dark for 30 min in a solution consisting of 10 ml cacodylate buffer (pH 5.1;0.1 M), 20 mg DAB and 0.1 ml of 1% hydrogen peroxide. The Kodak Wratten no. 46 filter is recommended for light-microscopical identification of labeled neurons since it is closely matched to the absorption spectrum of the DAB reaction product and consequently greatly increases the contrast of HRP-labeled neurons.

Animals↗
PubMed1983

Axonal transport in neuropathy.

Recent studies on the distribution of labeled endogenous proteins in the experimental neuropathies induced by streoptozotocin diabetes, galactose feeding, zinc pyridinethione, 2,5-hexanedione, acrylamide, and p-bromophenylacetylurea (BPAU) have demonstrated an impaired build up of retrogradely transported material derived from the more distal parts of peripheral nerve. In BPAU neuropathy the transport abnormality is strongly related to the degree of muscle weakness; following treatment with acrylamide the extent of the impairment is dose related. In both toxic conditions the transport abnormality is present well in advance of the first clinical signs of neuropathy. We therefore suggest that changes in retrograde axonal transport play an initial and important role in the development of many axonopathies.

Acrylamide↗
PubMedDate not supplied

The inferior olivary connections to the cerebellum in the rat studied by retrograde axonal transport of horseradish peroxidase.

Olivocerebellar projections were investigated in the rat using retrograde axonal transport of horseradish peroxidase. Discrete cell groups of the inferior olive were labelled, subsequent to injections in the paravermal region, the vermis, or the caudolateral hemisphere. Injections in the mid-rostrocaudal third of the paravermal area resulted in labelling of cells in the medial accessory olive (MAO), in cell group "b" at caudal levels, and in its lateral portion at mid-rostrocaudal levels. The rostral pole of the principal olive (PO), the dorsal accessory olive (DAO), and the dorsomedial cell column, were heavily labelled. By comparison, caudal paravermal injections resulted in labelling in the medial part of the mid-rostrocaudal levels of the MAO, but not in its caudal portion. The PO lamellae were labelled in their lateral half, excluding the lateral bend connecting them. Injections slightly lateral within this paravermal area gave no caudal MAO labelling, but did label cells in segments of both PO lamellae, medial to those in the previous case. From vermal injections, cell groups "b" and "c" of the caudal MAO were labelled, but no labelled cells were present in the PO. Subsequent to injections in the paramedian lobule, cells in the dorsal lamella of the PO were labelled. No cells of the MAO were labelled. These results are discussed in terms of specific labelling patterns and the general concepts of organization presently held for the olivocerebellar system.

Animals↗
PubMed1992

Influence of spinal cord transection on the presence and axonal transport of CGRP-, chromogranin A-, VIP-, synapsin I-, and synaptophysin-like immunoreactivities in rat motor nerve.

Using immunofluorescence and cytofluorimetric scanning (CFS), we investigated the short-term (1-7 days) influence of lower thoracic spinal cord transection on lumbar motor neurons. The content of calcitonin gene-related peptide- (CGRP) like immunoreactivity (LI), chromogranin A (Chr A)-LI, vasoactive intestinal polypeptide (VIP)-LI, Syn I-LI, and synaptophysin (p38)-LI in motor perikarya, and the anterograde and retrograde axonal transport of these substances in the sciatic nerve, were studied in nerve crush (6 h) experiments. During the week after transection, CGRP-LI in perikarya decreased, whereas Chr A-LI increased. VIP-LI, co-localized with Chr A-LI in motor perikarya, did not change after transection. The antero- and retrograde transport of CGRP-LI in the sciatic nerve, occurring in both motor and sensory axons, appeared unchanged in cytofluorimetric scanning (CFS) graphs, but the microscopical picture clearly showed that large motor axons had a decreased content of CGRP-LI at 3 and 7 days posttransection, whereas thinner axons were unchanged in fluorescence intensity. The anterograde transport of Chr A-LI, present in both motor and postganglionic adrenergic axons, was decreased 1 and 3 days after lesion, but returned to control by day 7. There was a marked decrease in anterograde transport of VIP-LI, present mainly in postganglionic sympathetic axons, at day 3, but at 7 days transport was normal. The amounts of transported p38, the synaptic vesicle marker, were in the normal range during the whole period. Syn I-LI accumulation anterogradely was somewhat decreased at 3 and 7 days posttransection, and at 1 day the retrograde accumulation was significantly increased. The results suggest that removal of supraspinal input to intact lower motor neurons causes alterations in metabolism and axonal transport of organelle-associated substances, partly probably related to the complex pattern of transmitter leakage from degenerating, descending nerve terminals. These alterations appear to take place also in postganglionic sympathetic neurons in the sciatic nerve, that originate in the lumbar sympathetic chain.

Acetylcholinesterase↗
PubMed1984

Increase in axonal transport in demyelinating optic nerve fibres in the mouse infected with Semliki Forest virus.

Since the integrity of myelin and axon is closely linked with the transport of substances along the axon, changes in the fast and slow axonal transport in the demyelinating optic nerves of mice infected with Semliki Forest virus were studied. Radioactive analysis of the superior colliculi and the optic nerves was thus made following different survival times after an intravitreal injection of tritiated proline by autoradiographic and liquid scintillation counting techniques. The amounts of both the fast and slow axonal transport of proteins were significantly higher in the optic nerves of mice infected with the virus than those found in the optic nerves of control mice. These results suggest that demyelinating fibres send a signal to the perikarya which then responds by synthesizing more proteins.

Animals↗