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PubMed1992

Assessment of slow axonal transport in lead-exposed rats.

To evaluate the effect of lead on slow axonal transport, mean transport velocity (Vmean) of radiolabeled proteins in the motor fibers of the sciatic nerve was calculated by simulating the distribution of radioactivity along the nerve 2 weeks after intraspinal injection of L-[35S] methionine in eight rats given drinking water containing lead acetate for 13 weeks. The transport of individual radiolabeled proteins was also inspected visually by fluorography. It was observed that the Vmean was significantly slowed in the lead-exposed rats and was correlated with blood lead concentration; fluorography indicated that the transport of neurofilament proteins and of tubulins was mildly retarded in the most severely affected lead-exposed rat. These findings suggest that slow axonal transport was impaired by lead. Further study using a large number of animals will be necessary to confirm the findings of the present study.

Animals↗
PubMed1981

Incorporation of axonally transported glycoproteins into axolemma during nerve regeneration.

The insertion of axonally transported fucosyl glycoproteins into the axolemma of regenerating nerve sprouts was examined in rat sciatic motor axons at intervals after nerve crush. [(3)H]Fucose was injected into the lumbar ventral horns and the nerves were removed at intervals between 1 and 14 d after labeling. To follow the fate of the "pulse- labeled" glycoproteins, we examined the nerves by correlative radiometric and EM radioautographic approaches. The results showed, first, that rapidly transported [(3)H]fucosyl glycoproteins were inserted into the axolemma of regenerating sprouts as well as parent axons. At 1 d after delivery, in addition to the substantial mobile fraction of radioactivity still undergoing bidirectional transport within the axon, a fraction of label was already associated with the axolemma. Insertion of labeled glycoproteins into the sprout axolemma appeared to occur all along the length of the regenerating sprouts, not just in sprout terminals. Once inserted, labeled glycoproteins did not undergo extensive redistribution, nor did they appear in sprout regions that formed (as a result of continued outgrowth) after their insertion. The amount of radioactivity in the regenerating nerves decreased with time, in part as a result of removal of transported label by retrograde transport. By 7-14 d after labeling, radioautography showed that almost all the remaining radioactivity was associated with axolemma. The regenerating sprouts retained increased amounts of labeled glycoproteins; 7 or 14 d after labeling, the regenerating sprouts had over twice as much of radioactivity as comparable lengths of control nerves or parent axons. One role of fast axonal transport in nerve regeneration is the contribution to the regenerating sprout of glycoproteins inserted into the axolemma; these membrane elements are added both during longitudinal outgrowth and during lateral growth and maturation of the sprout.

Animals↗
PubMed1987

Alterations in retrograde axonal transport in streptozocin-induced diabetic rats.

Retrograde axonal transport in the sciatic nerve of rats with streptozocin-induced diabetes was studied by the [3H]N-succinimidyl propionate [( 3H]NSP) method. The accumulation of retrogradely transported labeled proteins in the dorsal root ganglia and the ventral horn of spinal cord 1 day after [3H]NSP injection was not statistically significantly different from controls in rats diabetic for 1 or 14 days at the time of [3H]NSP injection. However, accumulation of labeled proteins in the dorsal root ganglia 7 days after [3H]NSP injection was reduced by 35% and transport to the ventral horn of spinal cord 7 days after [3H]NSP injection was reduced by 70% at the same time points. Partial control of the diabetes with insulin resulted in a partial reversal of these deficits. The early occurrence of defects in retrograde transport suggests that such defects may play a role in the pathogenesis of the neuropathy.

Animals↗
PubMed1991

Conserved beta-tubulin binding domain for the microtubule-associated motors underlying sperm motility and fast axonal transport.

An antiserum against tubulin, NS20, has been previously shown to inhibit anterograde and retrograde axonal transport by 50% in vivo and in vitro. We report here that Protein A purified NS20 antibodies also attenuate sperm motility by 50% in demembranated sea urchin sperm. This inhibition is absorbed out by preincubating the NS20 antibodies with a biochemically purified porcine microtubule preparation, with recombinant Trypanosoma beta- (but not alpha-) tubulin and most specifically, with a 37 amino acid (a.a.) synthetic peptide corresponding to a domain near (but not including) the porcine beta-tubulin C terminus. Furthermore, addition of this beta-tubulin peptide alone is sufficient to attenuate motility by 50% in demembranated sperm, indicating that this critical 37a.a. NS20 antigen is a motor binding domain. Together, the results suggest that at least two phenotypically distinct forms of microtubule-based motility, axonal transport and flagellar beating, are homologous at the fundamental level of the microtubule domains (the beta-tubulin peptide and we suggest a distinct but similarly located alpha-tubulin domain) mediating the attachment of tubulin-associated motors.

Amino Acid Sequence↗
PubMed1998

Real-time imaging of the axonal transport of granules containing a tissue plasminogen activator/green fluorescent protein hybrid.

A hybrid protein, tPA/GFP, consisting of rat tissue plasminogen activator (tPA) and green fluorescent protein (GFP) was expressed in PC12 cells and used to study the distribution, secretory behavior, and dynamics of secretory granules containing tPA in living cells with a neuronal phenotype. High-resolution images demonstrate that tPA/GFP has a growth cone-biased distribution in differentiated cells and that tPA/GFP is transported in granules of the regulated secretory pathway that colocalize with granules containing secretogranin II. Time-lapse images of secretion reveal that secretagogues induce substantial loss of cellular tPA/GFP fluorescence, most importantly from growth cones. Time-lapse images of the axonal transport of granules containing tPA/GFP reveal a surprising complexity to granule dynamics. Some granules undergo canonical fast axonal transport; others move somewhat more slowly, especially in highly fluorescent neurites. Most strikingly, granules traffic bidirectionally along neurites to an extent that depends on granule accumulation, and individual granules can reverse their direction of motion. The retrograde component of this bidirectional transport may help to maintain cellular homeostasis by transporting excess tPA/GFP back toward the cell body. The results presented here provide a novel view of the axonal transport of secretory granules. In addition, the results suggest that tPA is targeted for regulated secretion from growth cones of differentiated cells, strategically positioning tPA to degrade extracellular barriers or to activate other barrier-degrading proteases during axonal elongation.

Animals↗
PubMed2005

Endothelin-1 modulates anterograde fast axonal transport in the central nervous system.

Anterograde fast axonal transport (FAxT) maintains synaptic function and provides materials necessary for neuronal survival. Localized changes in FAxT are associated with a variety of central nervous system (CNS) neuropathies, where they may contribute to inappropriate remodeling, a process more appropriately involved in synaptic plasticity and development. In some cases, developmental remodeling is regulated by localized secretion of endothelins (ETs), neuroinflammatory peptides that are also pathologically elevated in cases of neurologic disease, CNS injury, or ischemia. To investigate the potential role of ETs in these processes, we decided to test whether locally elevated endothelin-1 (ET-1) modulates FAxT in adult CNS tissues. We used the established in vivo rat optic nerve model and a novel ex vivo rat hippocampal slice model to test this hypothesis. In vivo, exogenously elevated vitreal ET-1 significantly affected protein composition of FAxT-cargos as well as the abundance and peak delivery times for metabolically-labeled proteins that were transported into the optic nerve. Proteins with molecular weights of 139, 118, 89, 80, 64, 59, 51, 45, 42, 37, and 25 kDa were evaluated at injection-sacrifice intervals (ISIs) of 24, 28, 32, and 36 hr. In acute hippocampal slices maintained on nonvascular supplies of glucose and oxygen, ET-1 significantly decreased the distance traveled along the Schaffer collateral tract by nonmetabolically-labeled lipid rafts at 5 and 10 min after pulse-labeling. In both models, ET-1 significantly affected transport or targeted delivery of FaxT-cargos, suggesting that ET-1 has the potential to modulate FAxT in adult CNS tissues.

Animals↗
PubMed1994

Retrograde axonal transport of the alpha-subunit of the GTP-binding protein GZ in mouse sciatic nerve: a potential pathway for signal transduction in neurons.

We have utilized antibodies against the alpha subunit of GZ in fluorescence immunohistochemistry to determine whether this GTP-binding protein can translocate along nerves by intra-axonal transport. After ligation of the mouse sciatic nerve we found an increase in GZ-like immunoreactivity on the proximal and distal side with time, suggesting that the alpha subunit undergoes orthograde axonal transport and also returns to the cell body by retrograde axonal transport in the sciatic nerve. Unlike the retrograde transport of Gi alpha, shown in a previous study to be present in most sciatic axons, GZ alpha only accumulated in a subpopulation of axons, suggesting that different G-proteins could convey information specific to neuronal subtypes. These results support our proposal that GZ may play a second messenger role in communicating information from the terminals back to cell bodies. Gi alpha and GZ alpha may be representative of relatively stable signalling molecules by which the signal from some neurotrophic molecules can be translocated from the neuron periphery to the cell body without the need for the retrograde transport of the neurotrophic factor itself.

Amino Acid Sequence↗
PubMed1979

Blockade of rapid axonal transport. Effect of intraocular pressure elevation in primate optic nerve.

After acute intraocular pressure (IOP) elevation, an induced disturbance of rapid axonal transport at the optic nerve head began within three hours at the IOP levels tested. The accumulation of radioactive label at the scleral lamina cribrosa increased with time of IOP elevation. There was a 60% decrease in the amount of transported material in the optic nerve, tract, and lateral geniculate body (LGN). Detailed analysis suggests that this decrease is not due to a simple slowdown of transport, but results from a total block of rapid transport in some axons, with no impairment in other axons. This total blockade of rapid transport by elevated IOP in involved axons differs from the apparent slowdown of transport in experimental papilledema, and the difference may explain the response of ganglion cells to the two conditions.

Animals↗
PubMed1986

Immunocytochemical studies on axonal transport in adrenergic and cholinergic nerves using cytofluorimetric scanning.

The axonal transport of adrenergic and cholinergic axonal organelles in rat sciatic nerve has been studied using a cytofluorimetric scanning (CFS) technique. This technique gives quantitative data on material which accumulates in a nerve relative to a crush, as well as morphological and morphometrical information about the accumulated axons in the nerve. One important advantage is that several substances can be measured in the same nerve segment, thus reducing the number of animals needed. The substances must be made fluorescent, and in this study we have investigated noradrenaline (NA), using formaldehyde induced fluorescence, and dopamine beta-hydroxylase (DBH), tyrosine hydroxylase (TH), neuropeptide Y (NPY) and two cholinergic vesicle components (a transmembrane glycoprotein and synapsin I) using indirect immunofluorescence. The antisera used for labelling immunoreactive material (IR) were produced in rabbit or goat (DBH). In adrenergic axons NA, DBH-IR and TH-IR accumulated with time after crushing the nerve as described earlier with biochemical techniques. After reserpine, the amounts of amine granules transported distally in the sciatic nerve initially fell, but recovered during day 2 after reserpine. At day 4 the amount of NA and DBH-IR which was transported distally in the axons was supranormal, 160% and 140% of control, respectively, but the level of NPY-IR was not increased, even falling to subnormal at day 4, indicating different mechanisms for regulating the synthesis of DBH and NPY which are suggested to co-exist in axonal adrenergic large dense core vesicles. In cholinergic motor axons organelles, recognized by rabbit-anti-cholinergic synaptic vesicles-antiserum (RASVA) and by anti-synapsin I-antiserum, are transported distally at a rapid rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic Fibers↗
PubMed1977

Axonal transport of organelles visualized by light microscopy: cinemicrographic and computer analysis.

Rapid movements of intra-axonal organelles in acutely isolated single myelinated fibers from bullfrog sciatic nerve were visualized by dark-field microscopy. The movements were recorded by cinemicrography, and analyzed by computer-based methods. The movements are saltatory and bidirectional, but each particle moves mainly in a single direction. For more than 90% of the particles, the predominant movement direction is retrograde, i.e. toward the cell body. Quantitative measurements on a variety of parameters of the organelle movements are presented. Different particles in the same axon show a broad range of mean speeds. The average mean speed of movement in the retrograde direction at 28 degrees C was 1.08 micrometer/sec (S.D. - 0.41), equivalent to an axonal transport rate of 93 mm/day. Disperse distributions were also found for other parameters such as the instantaneous velocities of individual particles. Quantal velocities, periodic movement patterns, and specific 'channels' were not detected. When the data from a population of particles is treated statistically, the average mean speed, the distribution of velocities, and other statistical parameters are found to be similar in different axons studied at the same temperature. Direct microscopical observation of axonal organelle movement is a technique which provides information about axonal transport which is different from and complementary to that obtained from enzyme accumulation of radioactive tracer methods.

Animals↗
PubMed1995

Defective axonal transport in a transgenic mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a degenerative disease of motor neurons, characterized by depositions of neurofilaments in the perikarya and proximal axons. The pathogenesis of ALS remains poorly understood, but two lines of evidence suggest that neurofilament accumulation may play a causal role. First, transgenic mice that overexpress neurofilament proteins show motor neuron degeneration and, second, variant alleles of the neurofilament heavy-subunit gene (NF-H) have been found in some human ALS patients. To investigate how disorganized neurofilaments might cause neurodegeneration, we examined axonal transport of newly synthesized proteins in mice that overexpress the human NF-H gene. We observed dramatic defects of axonal transport, not only of neurofilament proteins but also of other proteins, including tubulin and actin. Ultrastructural analysis revealed a paucity of cytoskeletal elements, smooth endoplasmic reticulum and especially mitochondria in the degenerating axons. We therefore propose that the neurofilament accumulations observed in these mice cause axonal degeneration by impeding the transport of components required for axonal maintenance, and that a similar mechanism may account for the pathogenesis of ALS in human patients.

Amyotrophic Lateral Sclerosis↗
PubMed1985

Axonal regeneration in wobbler motor neuron disease: quantitative histologic and axonal transport studies.

The regenerative capacity of the cervical anterior horn cells was studied at 4 and 7 days following forelimb nerve crush in 19 wobbler mice and 18 normal littermates. Quantitative histologic and radiolabeled axonal transport techniques showed that the axotomized neurons of the wobbler mouse supported active axonal elongation. However, the average axon outgrowth rate determined by histologic technique was diminished by 25% and the fastest axon outgrowth rate determined by axonal transport technique was also decreased by 30% in wobbler mice as compared to controls. The distal labeled peak was absent in the wobbler mouse at 7 days, indicating that the regeneration rate of individual axons was widely dispersed. Histologic studies also showed that the wobbler axons grew slowly. This study suggests that axonal regeneration does occur in motor neurons undergoing a primary neuronopathy. However, the regenerative capacity was reduced and this appears to reflect an impairment of functional integrity in the anterior horn cells of the wobbler mouse.

Animals↗
PubMed1986

Axonal transport of monoclonal antibodies.

Three monoclonal antibodies against rat brain synaptosomes, produced by conventional hybridoma techniques, were screened for their ability to undergo uptake and axonal transport in vivo. Injections of ascitic fluid or of purified immunoglobulin G (IgG) were made into the vitreal chamber of the eye in anesthetized rats to test for anterograde transport in retinal afferents to the contralateral superior colliculus. Retrograde transport by facial nucleus motoneurons was evaluated after injections of antibody into the mystatial vibrissal skin and musculature. Transported immunoglobulins were localized in tissue sections using a modification of the peroxidase-antiperoxidase technique. One monoclonal antibody, S-2C10, was found to undergo anterograde transport in retinal ganglion cells and retrograde axonal transport in facial motoneurons. Transported immunoglobulins were detectable even after injections of dilute antibody solution (0.01-0.05% IgG), and the uptake-transport process for this antibody appeared saturable. Two other antibodies tested, S-4E9 and S-1G10, exhibited the ability to undergo retrograde transport, but only after injections at relatively high antibody concentrations (greater than or equal to 1.0% IgG). Neither of these antibodies was shown to undergo anterograde transport. Following retrograde transport in motoneurons, the S-2C10 antibody was localized in neuronal perikarya, proximal dendrites, and the adjacent neuropil of the facial motor nucleus. In contrast, the S-4E9 and S-1G10 antibodies were localized in punctate granules within neuronal cell somata following transport. The findings suggest that the uptake-transport process for the S-2C10 antibody is mediated by adsorptive endocytosis following binding of the antibody to a plasma membrane component (or components) present in somadendritic and nerve terminal membranes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Acrylamide neuropathy and changes in the axonal transport and muscular content of the molecular forms of acetylcholinesterase.

Acetylcholinesterase (AChE) is present in nervous and muscular tissues of normal chickens in four main molecular forms (G1, G2, G4, and A12), distinguishable by sedimentation analysis. In the sciatic nerve of acrylamide-poisoned chickens, the anterograde axonal transport of A12 AChE was reduced by 60%, and that of G4 by 21%, compared to control values whereas the slow axoplasmic transport of G1 and G2 was unaffected. Regarding the leg muscles, only the tibialis anterior revealed dramatic alterations in the distribution of it AChE forms coinciding with a large reduction in the number of nerve endings. In acrylamide poisoning, the AChE molecular forms were considered as very sensitive markers of both axonal transport phases and of the innervation state. Our results support the hypothesis that a defect in the fast axonal transport of proteins might be involved in the degeneration process of the disease.

Acetylcholinesterase↗
PubMed1994

Disruption of fast axonal transport in vivo leads to alterations in Schwann cell gene expression.

Following nerve injury, Schwann cells distal to the site of injury down-regulate genes associated with myelination. We hypothesized that at least some of these alterations were due to the loss of ongoing axon:Schwann cell homeostatic signals, as opposed to loss of physical contact and/or inflammatory responses. To directly test this hypothesis, we perturbed axonal physiology by selectively blocking fast axonal transport via locally cooling the sciatic nerve to 5-8 degrees C (a cold block). Immunostaining with the monoclonal antibody ED1, which recognizes mononuclear phagocytic cells, demonstrated that macrophages did not invade the cold-blocked nerve, indicating the lack of an inflammatory response. Morphological studies demonstrated that the nerve distal to the cold block showed no signs of Wallerian degeneration, with maintenance of normal axon and myelin profiles, and confirmed the absence of invading macrophages. Thus, any effects of a cold-block treatment were not likely due to inflammatory responses or to loss of physical contact between axons and Schwann cells. To determine whether this treatment affected Schwann cell phenotype, we examined expression of the major myelin protein P0, and p75 NGF receptor, both of which are regulated as a function of axon:Schwann cell interactions. Levels of p75 NGF receptor mRNA were unaffected by the cold block, while p75 NGF receptor protein levels were increased in the region of the nerve immediately adjacent to the cold block, presumably reflecting protein accumulation as a consequence of the block to fast axonal transport. In contrast, levels of P0 mRNA were decreased in the distal nerve in a fashion that indicated modulation of Schwann cell phenotype as a function of local axonal microenvironment. These data therefore suggest that P0 and p75 NGF receptor are regulated as a function of two different aspects of Schwann cell:axon communication. Furthermore, these data demonstrate that the presence of axon:Schwann cell contact alone is insufficient to maintain Po gene expression and indicate that at least some myelin-specific Schwann cell responses are dependent upon ongoing biochemical signals generated by the axon and maintained by fast axonal transport.

Animals↗
PubMed1999

Axonal transport and distribution of immunologically distinct kinesin heavy chains in rat neurons.

The functional significance of biochemical and immunochemical heterogeneity in neuronal kinesin remains uncertain. Confocal laser scanning microscopy, cytofluorimetric scanning, and immunoblots were used for quantitative analyses of axonal transport and cellular distribution of immunochemically distinct kinesin heavy chain isoforms (H1 and H2) in rat peripheral nerve and spinal cord. H1 and H2 immunoreactivities (IR) were observed in axons proximal to a crush as early as 1 hr after the crush operation and increased linearly with time, consistent with fast axonal transport of both. Only approximately 10% of the proximal accumulations of H1-IR and H2-IR accumulated distal to the crush, in contrast to synaptophysin-IR (approximately 70%). H2-IR was widely present in peripheral nervous system and virtually colocalized with synaptic vesicle proteins synaptophysin, synaptobrevin I, and SNAP-25 and two neuropeptides [calcitonin gene-related peptide (CGRP) and substance P (SP)], although H2-IR was weaker in spinal cord terminals. In contrast, H1-IR appeared preferentially enriched in large axons, probably motor and large sensory neurons, which contained synaptophysin-IR, synaptobrevin I-IR, SNAP-25-IR, and CGRP-IR. However, H1-IR was weak or absent from SP-containing thin and medium-sized axons. In addition, H1-IR appeared to be absent from spinal cord nerve terminals. H1- and H2-IR kinesins are both transported with fast axonal transport, and comparatively small amounts of kinesins are retrogradely transported. H2 was widely distributed in motor, sensory, and sympathetic neurons, whereas H1 was enriched in large motor and sensory neurons.

Animals↗
PubMed2006

Essential role of somatic and synaptic protein synthesis and axonal transport in long-term synapse-specific facilitation at distal sensorimotor connections in Aplysia.

To investigate further the cellular mechanisms underlying long-term facilitation (LTF) and long-term synapse-specific facilitation (LTSSF), we studied the role of axonal transport and somatic and synaptic protein synthesis at proximal and distal synapses of Aplysia siphon sensory neurons (SNs). The long soma-synapse distances (2.5 to 3 cm) of the SN distal synapses impose important temporal and mechanistic constraints on long-term facilitation and on intracellular signaling. Excitatory postsynaptic potentials (EPSPs) evoked by SNs in central and peripheral siphon motor neurons were used to assay LTF 24-30 h after various pharmacological treatments. Inhibition of protein synthesis via anisomycin application at either the SN soma or distal synapses blocked the induction of LTF and LTSSF normally produced by synaptic application of the facilitating transmitter serotonin (5-hydroxytryptamine). Further, disruption of axonal transport by application of nocodazole to the isolated siphon nerve completely blocked LTF at distal synapses. These results indicate an essential role for somatic and synaptic protein synthesis and active axonal transport in LTSSF at distal synapses, and raise intriguing questions for current synaptic marking/capture models of synapse specificity and LTF.

Animals↗
PubMed2002

Fast axonal transport: a site of acrylamide neurotoxicity?

The cellular and molecular site and mode of action of acrylamide (ACR) leading to neurotoxicity has been investigated for four decades, without resolution. Although fast axonal transport compromise has been the central theme for several hypotheses, the results of many studies appear contradictory. Our analysis of the literature suggests that differing experimental designs and parameters of measurement are responsible for these discrepancies. Further investigation has demonstrated consistent inhibition of the quantity of bi-directional fast transport following single ACR exposures. Repeated compromise in fast anterograde transport occurs with each exposure. Modification of neurofilaments, microtubules, energy-generating metabolic enzymes and motor proteins are evaluated as potential sites of action causing the changes in fast transport. Supportive and contradictory data to the hypothesis that deficient delivery of fast-transported proteins to the axon causes, or contributes to, neurotoxicity are critically summarized. A hypothesis of ACR action is presented as a framework for future investigations.

Acrylamide↗