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PubMed1993

Axonal transport and morphological changes following nerve compression. An experimental study in the rabbit vagus nerve.

Axonal transport and morphological changes were studied in the rabbit vagus nerve after the nerves had been subjected to compression at either 0, 50 or 200 mmHg for two hours. Slow axonally transported proteins, tubulin and actin, were radiolabelled with 35S-methionine two, seven or 14 days after the injury and the distribution of radiolabelled tubulin and actin within component b of slow transport was measured three days later by densitometric analysis of fluorographs of polyacrylamide gel. No significant differences were found in the distribution of tubulin two (50 and 200 mmHg) or seven (200 mmHg) days after injury, but at 14 days (200 mmHg) there was significantly increased radiolabelling of tubulin relative to actin in the nerve 60 to 70 mm from the nodose ganglion. Morphometric measurements of the nerve cell bodies two days after the compression injury at 200 mmHg revealed no significant changes. Previous work has shown that morphological changes, similar to those found after axotomy, were present in nerve cell bodies seven days after a compression injury. This, taken together with the present results, indicates that compression can induce both morphological and biochemical changes in the neurone. The altered axonal transport of tubulin associated with nerve injury follows a slower time course and does not precede the morphological changes. The findings may be of relevance when discussing the double crush syndrome.

Actins↗

PubMed1980

Relation of somal lipid synthesis to the fast axonal transport of protein and lipid.

The role of somal lipid synthesis in the fast axonal transport of protein and lipid was examined in vitro utilizing spinal/sciatic nerve preparations of bullfrog. Inhibition of phospholipid synthesis in dorsal root ganglia by the amphiphilic cation, fenfluramine (0.1-2.0 mM) was monitored as decreased incorporation of [3H]choline into phosphatidyl choline. This inhibition was directly proportional to a decrease in the amount of [3H]protein undergoing fast axonal transport, the two variables being related by a slope close to unity. [3H]Choline-labeled lipid undergoing fast transport in the axon was unaffected by inhibition of somal phospholipid synthesis. Levels of fenfluramine up to 1.0 mM had no effect on uptake or incorporation of [3H]leucine. Selective exposure of desheathed nerve trunks to 1.0 mM fenfluramine had no effect on [3H]protein translocation, indicating that local phospholipid synthesis is not required to maintain ongoing transport in the axon. Inhibition of cholesterol synthesis in the ganglia with the analog 20,25-diazacholesterol also resulted in depression of [3H]protein transport. Since synthesis of both phospholipid and cholesterol are required at the level of the ganglion, it is suggested that the initiation of fast axonal transport of protein is dependent on the assembly of lipoprotein structures in the soma.

Animals↗

PubMed1995

Calmodulin regulates fast axonal transport of squid axoplasm organelles.

The role of calmodulin (CaM) in organelle motility (fast axonal transport) in the axoplasm of the squid giant axon was evaluated directly using video-enhanced microscopy. Addition of 6 microM CaM to extruded squid axoplasm produced a 2.6-fold increase in the number of organelles moving per minute per unit area of axoplasm. When lower concentrations of CaM, including physiological concentration (2 micrograms/ml), were added to extruded axoplasm, the number of organelles moving was equally increased. CaM had no significant effect on the mean velocity of organelle translocations. The stimulatory effect of CaM was reduced significantly by the CaM inhibitors melittin (36 microM) and trifluoperazine (50 microM). Parvalbumin, a high-affinity calcium binding protein, did not stimulate motile activity. These results suggest that CaM is a positive regulator of fast axonal transport. At the molecular level, this regulation may involve microtubule-and/or actin-based motor proteins. Several possible molecular mechanisms are proposed.

Animals↗

PubMed1984

Axonal transport blockade and denervation have qualitatively different effects upon skeletal muscle metabolism.

The activity and isoenzyme pattern of muscle lactic dehydrogenase (LDH) was measured at different times after axonal transport blockade by colchicine or after denervation. After denervation, total LDH activity decreased and the isoenzyme pattern was altered, LDH-1 being the most affected form. In contrast, after axonal transport blockade there was a decrease in LDH activity but the isoenzyme pattern was not modified. Denervation abolishes both nerve-evoked muscle activity and the release of neuro trophic substances from the nerve whereas colchicine blocks axonal transport without affecting the nerve capacity to conduct action potentials or neuromuscular transmission. It is then concluded that nerve-evoked muscle activity is the most important factor in the regulation of muscle LDH isoenzyme distribution. On the other hand, muscle metabolism can also be regulated by axonally transported molecules. The results presented here show that there is a qualitative difference between the effects of denervation and those of axonal transport blockade upon the muscle, since only denervation altered the isoenzyme pattern of muscle LDH.

Animals↗

PubMed1986

Effects of nerve compression on fast axonal transport in streptozotocin-induced diabetes mellitus. An experimental study in the sciatic nerve of rats.

The hypothesis that nerves in diabetes mellitus exhibit an increased susceptibility to compression was experimentally tested. Inhibition of fast axonal transport was induced by local compression in sciatic nerves of rats with streptozotocin-induced diabetes mellitus. Fast anterograde axonal transport was measured after application of 3H-leucine to the motor neurone cell bodies in the spinal cord. The sciatic nerve was subjected to local, graded compression in vivo by a small compression chamber. The amount of accumulation of proteins was quantified by calculation of a transport block ratio. Compression at 30 mm Hg for 3 h induced a significantly greater (p less than 0.05) accumulation of axonally transported proteins at the site of compression in nerves of diabetic animals (transport block ratio: 1.01 +/- 0.35; n = 7) than in nerves of controls (0.67 +/- 0.16; n = 7). Accumulation was significantly higher in ligature experiments of both control (1.34 +/- 0.44; n = 8; p less than 0.01) and diabetic animals (1.45 +/- 0.30; n = 8; p less than 0.05), indicating that the block of transport in compressed nerves was incomplete. Neither sham compressed diabetic (0.50 +/- 0.09; n = 6) nor control (0.49 +/- 0.11; n = 6) nerves showed any block of axonal transport. The possible causes of the increased inhibition of fast axonal transport in diabetic rats are discussed. The results indicate that diabetes may lead to an increased susceptibility of peripheral nerves to compression.

Animals↗

PubMed1985

Characterization of the binding properties and retrograde axonal transport of a monoclonal antibody directed against the rat nerve growth factor receptor.

We have demonstrated in vitro and in vivo the specific binding of a monoclonal antibody to the rat nerve growth factor (NGF) receptor. Previous work had shown that this antibody, designated 192-IgG, does not compete with NGF for binding to the NGF receptor of PC12 cells, but instead interacts with the receptor to increase NGF binding to PC12 cells (Chandler, C. E., L. M. Parsons, M. Hosang, and E. M. Shooter, 1984, J. Biol. Chem., 259:6882-6889). In the present study, a solid-phase separation assay verified the specific formation of a ternary complex of 192-IgG, the NGF receptor, and NGF: 125I-labeled 192-IgG precipitated from solution only when incubated with both solubilized NGF receptor and NGF covalently linked to a solid phase (Sepharose 4B). Filtration assays using plasma membrane preparations of various tissues showed strict correlation of 125I-192-IgG and 125I-labeled NGF binding; only membranes obtained from superior cervical ganglion bound significant amounts of the monoclonal antibody and NGF. Injection of 125I-192-IgG into the rat anterior eye chamber led to accumulation of intact antibody molecules in the ipsilateral superior cervical ganglion, indicating retrograde axonal transport of 125I-192-IgG from the neuronal termini, located at the iris, to the cell bodies situated in the ganglion. The time course and saturation characteristics of 125I-192-IgG retrograde transport were very similar to those previously reported for 125I-NGF transport, indicating that 192-IgG can be internalized and transported by the same mechanisms as is NGF. Consistent with results of the in vitro binding assays, 192-IgG and NGF failed to compete for retrograde transport and were actually co-transported. Retrograde axonal transport of 192-IgG appears to be species specific, since 125I-192-IgG was transported in the rat, but not in mice, gerbils, hamsters, or guinea pigs. These results establish monoclonal antibody 192-IgG as a specific probe for the rat NGF receptor in vitro and in vivo.

Animals↗

PubMed2000

Molecular mechanisms regulating the retrograde axonal transport of neurotrophins.

Neurotrophins are released from target tissues following neural innervation and bind to specific receptors situated on the nerve terminal plasma membrane. The neurotrophin-receptor complex undergoes retrograde axonal transport towards the cell soma, where it signals to the nucleus. This process allows neurotrophins to perform their numerous functions, which include the promotion of neuronal survival and the outgrowth of axons towards certain target tissues. The molecular events controlling each of the components of retrograde axonal transport are beginning to become defined. There is good evidence for the participation of phosphatidylinositol 3-kinase, phosphatidylinositol 4-kinase and the actin cytoskeleton in neurotrophin retrograde axonal transport in vivo. It also appears that the retrograde motor protein dynein mediates the retrograde axonal transport in vivo of neurotrophins such as nerve growth factor. This review discusses the role of the neurotrophin receptors in binding and axonal transport, the endocytic processes required for neurotrophin internalization, the targeting and trafficking of neurotrophins, and the propagation of neurotrophin-induced signals along the axon.

Animals↗

PubMed2002

Phosphatidylinositol kinase enzymes regulate the retrograde axonal transport of NT-3 and NT-4 in sympathetic and sensory neurons.

Phosphatidylinositol 3-kinase (PI3-kinase) and phosphatidylinositol 4-kinase (PI4-kinase) enzymes are an important family of signaling molecules that have been implicated in the regulation of intracellular vesicle trafficking. It has previously been shown that PI3-kinase and PI4-kinase enzymes regulate neuronal survival and the retrograde axonal transport of nerve growth factor in sympathetic and sensory neurons. We have extended these studies to examine the role these enzymes play in the regulation of the retrograde axonal transport of neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) in sympathetic and sensory neurons in vivo. Wortmannin (0.1 nmol/eye), a PI3-kinase and PI4-kinase antagonist, reduced the amount of (125)I-NT-3 retrograde transport in sympathetic neurons by approximately 50% and (125)I-NT-4 in sympathetic neurons by approximately 40% and sensory neurons by approximately 20%. The PI3-kinase antagonist LY294002 (100 nmol/eye) reduced the retrograde axonal transport of (125)I-NT-4 in sympathetic and sensory neurons, and (125)I-NT-3 in sympathetic neurons. Phenylarsine oxide (PAO), a PI4-kinase antagonist, significantly inhibited (125)I-NT-4 retrograde axonal transport in sympathetic and sensory neurons. These results show that wortmannin-sensitive PI3-kinases and PI4-kinases may be involved in NT-3 and NT-4 retrograde axonal transport. The retrograde axonal transport of neurotrophic factors in sympathetic and sensory neurons in vivo appears to depend upon the activation of different receptors and second messenger cascades at the nerve terminal.

Androstadienes↗

PubMed2005

The GTPase dMiro is required for axonal transport of mitochondria to Drosophila synapses.

We have identified EMS-induced mutations in Drosophila Miro (dMiro), an atypical mitochondrial GTPase that is orthologous to human Miro (hMiro). Mutant dmiro animals exhibit defects in locomotion and die prematurely. Mitochondria in dmiro mutant muscles and neurons are abnormally distributed. Instead of being transported into axons and dendrites, mitochondria accumulate in parallel rows in neuronal somata. Mutant neuromuscular junctions (NMJs) lack presynaptic mitochondria, but neurotransmitter release and acute Ca2+ buffering is only impaired during prolonged stimulation. Neuronal, but not muscular, expression of dMiro in dmiro mutants restored viability, transport of mitochondria to NMJs, the structure of synaptic boutons, the organization of presynaptic microtubules, and the size of postsynaptic muscles. In addition, gain of dMiro function causes an abnormal accumulation of mitochondria in distal synaptic boutons of NMJs. Together, our findings suggest that dMiro is required for controlling anterograde transport of mitochondria and their proper distribution within nerve terminals.

Animals↗

PubMed1986

Analysis of the carbohydrate composition of axonally transported glycoconjugates in sciatic nerve.

Glycosidase enzyme digestion in combination with postembedding lectin cytochemistry was used to study the carbohydrate composition of axonally transported glycoproteins. A cold block procedure for the interruption of axonal transport was employed to increase selectively the population of anterograde moving components on the proximal side of the transport block. Electron-microscopic observations revealed that a cold block applied to the sciatic nerve of an anesthetized rat produced an increase in axonal smooth membrane vesicles at a site directly proximal to the cold block. Postembedding lectin cytochemistry of the sciatic nerve demonstrated a substantial increase in concanavalin A (Con A), wheat germ agglutinin (WGA), and succinylated WGA binding sites in axons directly proximal to the cold block. Endoglycosidase H (endo H) digestion prior to lectin cytochemistry characterized a large population of the axonally transported Con A binding sites as polymannose and/or hybrid N-linked oligosaccharides (endo H-susceptible). A distinct population of neuraminidase-resistant WGA binding sites was also found in axons directly proximal to the transport block. The concomitant increase in smooth membrane vesicles and lectin binding sites in axons at the transport block supports the hypothesis that a system(s) of smooth membrane inside the axon is involved in the transport of glycoproteins from the cell soma to their cell surface destinations. Results of glycosidase digestions and lectin cytochemistry experiments suggest that many of the axonally transported glycoprotein carbohydrates are polymannose and/or hybrid N-linked oligosaccharides. This observation is especially interesting in relation to our previous reports, which indicated that most lectin binding sites on the neuronal cell surface are composed of complex oligosaccharides.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2000

Taxol impairs anterograde axonal transport of microinjected horseradish peroxidase in dorsal root ganglia neurons in vitro.

We have investigated the effects of taxol on the axonal transport of horseradish peroxidase (HRP) in dorsal root ganglia (DRG) cells and their neuronal cytoskeleton. The former were analysed by microinjection of HRP into single DRG cells and the latter was studied by means of immunohistochemistry and cryo-electron microscopy. In cultured and untreated DRG cells, microinjected HRP was typically transported anterogradely several hundred micrometres along their neurites. Different exposure periods (1, 2 and 3 days) to taxol were analysed. The axonal transport of HRP in DRG cells was time-dependently impeded by taxol. After the drug had been washed out, a recovery of the axonal transport of HRP was observed and confirmed by quantitative analysis. Cryo-electron microscopy revealed an abnormal aggregation of axonal and cytoplasmic microtubules, associated with a decreased amount of cross-linking structures, in taxol-treated DRG cell cultures. After 3 days of taxol exposure, microtubule-associated proteins and Tau-protein were restricted to the cellular somata but the neurofilament network and tubulin-proteins seemed to be unaffected. Our results demonstrate, for the first time, an inhibition of anterograde axonal transport of HRP in single neurons by taxol. This effect is reversible and seems not to be caused by cellular damage, but is rather a consequence of an altered organisation of microtubules and/or microtubule-associated proteins.

Animals↗

PubMed2002

Axonal transport of neurofilaments in normal and disease states.

Neurofilaments are among the most abundant organelles in neurones. They are synthesised in cell bodies and then transported into and through axons by a process termed 'slow axonal transport' at a rate that is distinct from that driven by conventional fast motors. Several recent studies have now demonstrated that this slow rate of transport is actually the consequence of conventional fast rates of movement that are interrupted by extended pausing. At any one time, most neurofilaments are thus stationary. Accumulations of neurofilaments are a pathological feature of several human neurodegenerative diseases suggesting that neurofilament transport is disrupted in disease states. Here, we review recent advances in our understanding of neurofilament transport in both normal and disease states. Increasing evidence suggests that phosphorylation of neurofilaments is a mechanism for regulating their transport properties, possibly by promoting their detachment from the motor(s). In some neurodegenerative diseases, signal transduction mechanisms involving neurofilament kinases and phosphatases may be perturbed leading to disruption of transport.

Axonal Transport↗

PubMed2000

Modulation of taurine uptake in the goldfish retina and axonal transport to the tectum. Effect of crushing the optic nerve or axotomy.

Although there are a great number of studies concerning the uptake of taurine in several tissues, the regulation of taurine transport has not been studied in the retina after lesioning the optic nerve. In the present study, isolated retinal cells of the goldfish retina were used either immediatly after cell suspension or in culture. The high-affinity transport system of [3H]taurine in these cells was sodium-, temperature- and energy-dependent, and was inhibited by hypotaurine and beta-alanine, but not by gamma-aminobutyric acid. There was a decrease in the maximal velocity (Vmax) without modifications in the substrate affinity (Km) after optic axotomy. These changes were mantained for up to 15 days after the lesion. The results might be the summation of mechanisms for providing extracellular taurine to be taken up by other retinal cells or eye structures, or regulation by the substrate taurine, which increases after lesioning the optic nerve. The in vivo accumulation of [3H]taurine in the retina after intraocular injection of [3H]taurine was affected by crushing the optic nerve or by axotomy. A progressive retinal decrease in taurine transport was observed after crushing the optic nerve, starting at 7 hours after surgery on the nerve. The uptake of [3H]taurine by the tectum was compensated in the animals that were subjected to crushing of the optic nerve, since the concentration of [3H]taurine was only different from the control value 24 hours after the lesion, indicating an efficient transport by the remaining axons. On the contrary, the low levels of [3H]taurine in the tectum after axotomy might be an index of the non-axonal origin of taurine in the tectum. Axonal transport was illustrated by the differential presence of [3H]taurine in the intact or crushed optic nerve. The uptake of [3H]taurine into retinal cells in culture in the absence or in the presence of taurine might indicate the existence of an adaptive regulation of taurine transport in this tissue, however taurine transport probably differentially occurs in specific populations of retinal cells. The use of a purified preparation of cells might be useful for future studies on the modulation of taurine transport by taurine in the retina and its role during regeneration.

Animals↗

PubMed2000

Hypophosphorylated neurofilament subunits undergo axonal transport more rapidly than more extensively phosphorylated subunits in situ.

Axonal transport of neurofilaments (NFs) has long been considered to be regulated by phosphorylation. We present evidence that in optic axons of normal mice, the rate of NF axonal transport is inversely correlated with the NF phosphorylation state. In addition to 200 kDa NF-H and 145 kDa NF-M, axonal cytoskeletons from CNS contained a range of phospho-variants of NF-H migrating between 160-200 kDa, and of NF-M migrating at 97-145 kDa. While 160 kDa phospho-variants of NF-H have been well characterized, we confirmed the identity of the previously-described 97 kDa species as a hypophospho-variant of NF-M since (1) pulse-chase metabolic labeling confirmed the 97 kDa species to be a new synthesis product that was converted by phosphorylation over time into a form migrating at 145 kDa, (2) the 97 kDa protein reacted with multiple NF-M antibodies, including one specific for hypophosphorylated NF-M, and (3) dephosphorylation converted NF-M isoforms to 97 kDa. Autoradiographic analyses following metabolic radiolabeling demonstrated that hypophosphorylated NF-H and NF-M isoforms underwent substantially more rapid transport in situ than did extensively phosphorylated isoforms, while NF-H subunits bearing a developmentally delayed C-terminal phospho-epitope transported at a rate slower than that of total 200 kDa NF-H. Differential transport of phospho-variants also highlights that these variants are not homogeneously distributed among NFs, but are segregated to some extent among distinct, although probably overlapping, NF populations, indicating that axonal NFs are not homogeneous with respect to phosphorylation state.

Animals↗

PubMed1992

Sabeluzole, a memory-enhancing molecule, increases fast axonal transport in neuronal cell cultures.

Morphological rearrangements, such as synapse number changes, have been observed in the adult mammalian brain after various experimental paradigms of learning and behavioral experience. The role of axonal transport in the physical translocation of material during this form of brain plasticity has not been fully appreciated. We show here by quantitative video microscopy that sabeluzole (R58735), a new memory-enhancing drug in humans, effectively increases fast axonal transport in rat neuronal cell cultures. Long-term incubation (24 hr) with sabeluzole in the concentration range between 0.1 and 1 microM increases both velocity and jump length of saltatory movements maximally by 20-30% in embryonic hippocampal neurons. Acute treatment only increases the velocity by 15-20%. Furthermore, the inhibition of axonal transport by 0.1 mM vanadate in N4 neuroblastoma cells is reversed by 1 microM sabeluzole. Observations on the kinesin-induced microtubule mobility in a reconstituted system show a 10% enhancement by sabeluzole at an optimal concentration of 2 microM, but no increase in kinesin ATPase activity. To our knowledge, this is the first pharmacological compound shown to increase fast axonal transport. The mechanism of fast axonal transport enhancement is discussed as a rationale for new therapeutic treatment in neuropathology.

Animals↗

PubMed1982

Biosynthesis, axonal transport and turnover of neuronal substance P.

In dorsal root ganglia substance P is synthesized ribosomally, probably via a precursor. A second peptide, apparently a modified form of substance P (8-11), is cosynthesized with substance P and transported with it down both dorsal roots and peripheral branches. Four times as much substance P-like immunoreactivity is transported peripherally as centrally. Only 30% of axonal substance P-like immunoreactivity is available for rapid axonal transport and this is transported at a rate of 4.9 mm h-1. Axonal transport is not necessary for substance P synthesis. Doses of anisomycin which inhibit CNS protein synthesis by more than 95% do not cause any fall in substance P levels over an eight-hour period in ganglia, spinal cord or brain, suggesting that turnover is slower than that of conventional transmitters. However, stimulation of the hindlimbs of these animals reduces substance P levels in the dorsal horn. The turnover rate of spinal cord substance P, estimated either by relating the amount transported down dorsal roots to that in terminals or by measuring the decline of substance P levels after intrathecal colchicine, is four to five days. The functional organization of the substance P neuron is discussed with particular reference to the maintenance of peptide levels in terminals.

Amino Acids↗

PubMed1991

Axonal transport reversal of acetylcholinesterase molecular forms in transected nerve.

Reversal of anterograde rapid axonal transport of four molecular forms of acetylcholinesterase (AChE) was studied in chick sciatic nerve during the 24-h period following a nerve transection. Reversal of AChE activity started approximately 1 h after nerve transection, and all the forms of the enzyme, except the monomeric ones, showed reversal of transport. The quantity of enzyme activity reversed 24 h after transection was twofold greater than that normally conveyed by retrograde transport. We observed no leakage of the enzyme at the site of the nerve transection and no reversal of AChE activity transport in the distal segment of the severed nerve, a result indicating that the material carried by retrograde axonal transport cannot be reversed by axotomy. Thus, a nerve transection induces both quantitative and qualitative changes in the retrograde axonal transport, which could serve as a signal of distal injury to the cell body. The velocity of reverse transport, measured within 6 h after transection, was found to be 213 mm/day, a value close to that of retrograde transport (200 mm/day). This suggests that the reversal taking place in severed sciatic nerve is similar to the anterograde-to-retrograde conversion process normally occurring at the nerve endings.

Acetylcholinesterase↗

PubMed2004

Glucocorticoid hormone (cortisol) affects axonal transport in human cortex neurons but shows resistance in Alzheimer's disease.

1 The changes of tissue sensitivity to glucocorticoids are associated with many pathological states including neurological diseases. In the present study, using a novel in vitro post-mortem tracing method on human brain slices, we demonstrated that cortisol, a major glucocorticoid hormone in humans, affected axonal transport both in the cortex neurons in four Alzheimer's disease (AD) patients and four nondemented controls. 2 Cortisol appeared to affect axonal transport of prefrontal cortex (PFC) and temporal cortex (TC) neurons in AD patients and controls in a dose-dependent way at concentrations of 30, 60, 120 and 240 microg dl(-1). 3 Higher doses of cortisol were needed for TC neurons to achieve a similar axonal transport effect as obtained in PFC neurons in AD patients. The maximum effect (Emax) on axonal transport was achieved in PFC slices at relatively low contraction (30-120 microg dl(-1)), while in TC slices, a maximum effect was only reached at relatively high concentrations (120-240 microg dl(-1)). 4 For PFC and TC slices from nondemented aging subjects, lower doses of cortisol (30-60 microg dl(-1)) on axonal transport were sufficient to achieve the maximum effect as compared to those used in AD brain slices, while levels of more than 60 microg dl(-1) of cortisol mostly depressed axonal transport. 5 These results suggest that glucocorticoid resistance, which is thought to contribute to the pathogenesis of a number of common human disorders, may exist in AD brains and play an important role in neuropathological mechanisms and dementia.

Aged↗