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PubMed1989

Junction between parent and daughter axons in regenerating myelinated nerve: properties of structure and rapid axonal transport.

The primary aim of this work was to investigate the properties of rapid axonal transport in regenerating myelinated axons in the sciatic nerve of Xenopus laevis, with particular attention to events at the junction between the proximal, intact axon (the "parent") and the distal, newly formed axon (the "daughter"). Morphological studies indicated that all myelinated axons initiated regeneration and that at least 80% of these axons regenerated at a rate of 1 mm/day or greater (20 degrees C). The ultrastructure of the junctional region was examined at regeneration times between 3 days and 20 weeks. The main qualitative change in the junctional axoplasm over this period was in its content of particulate organelles. At times up to 2 weeks regeneration, the junction contained abnormal numbers of 50 nm diameter vesicles and 10 nm granules. Between 2 and 5 weeks the junction showed in addition a peripheral rim of large membrane-bounded organelles around a central core of microtubules and neurofilaments. At longer times the numbers of large membrane-bounded organelles diminished and all junctions contained prominent accumulations of 10 nm granules. The rate of rapid axonal transport of protein was similar in parent and daughter axons. Compared to the parent axons, a 2-5 times greater amount of protein was deposited to a stationary phase in daughter axons. Specimens of nerve that were subjected to mechanical stress during the removal of the perineurium showed a large accumulation of rapidly transported protein in the region of the crush at regeneration times up to 40 days; some of the accumulated protein was subsequently transported retrogradely. Video microscopy of isolated axons supplied evidence that the transport deficit in mechanically stressed nerve was a partial block of anterograde vesicle transport, plus a reversal of anterograde transport, at the junction of parent with daughter axons. No structural changes were detected in mechanically stressed nerve. The results show that the junction between parent and daughter myelinated axons is a region with distinct morphology at which the dynamics of anterograde axonal transport may change dramatically.

Animals↗
PubMed1983

Axonal transport involvement in long-lasting synaptic modifications in Blatta orientalis.

To determine whether axonal transport plays a role in the establishment of long-lasting changes in synaptic transmission, the effects of colchicine on transport and on synaptic modifications induced by hyperactivity were studied in the nerve cord of the cockroach Blatta orientalis. Application of a lead weight on the insect's dorsum, and the consequent exaggerated use of antigravity reflexes, facilitated synaptic transmission along a particular nervous pathway in the metathoracic ganglion. Application of colchicine in the prothoracic ganglion reversibly blocked such synaptic facilitation and temporarily interfered with the transport of proteins along the cord. Five components of axonal transport, moving at 2, 10, 25, 75, and 150 mm/day, were altered by colchicine treatment with a temporal course that coincided with the reversible inhibition of synaptic facilitation. These results were brought about by colchicine acting directly on axonal transport at the level of the prothoracic ganglion, rather than on synaptic transmission measured at the metathoracic ganglion. The temporal correlation observed between the effects of colchicine on axonal transport and on synaptic facilitation strongly suggest that the transport process is essential for long-lasting synaptic modifications to take place.

Animals↗
PubMed2004

Mitogen-activated protein kinase regulates neurofilament axonal transport.

Mitogen-activated protein kinase (MAP) kinase plays a pivotal role in the development of the nervous system by mediating both neurogenesis and neuronal differentiation. Here we examined whether p42/44 MAP kinase plays a role in axonal transport and the organization of neurofilaments (NFs) in axonal neurites. Dominant-negative p42/44 MAP kinase, anti-MAP kinase antisense oligonucleotides and the MAP kinase inhibitor PD98059 all reduced NF phospho-epitopes and inhibited anterograde NF axonal transport of GFP-tagged NF subunits in differentiated NB2a/d1 neuroblastoma cells. Expression of constitutively active MAP kinase and intracellular delivery of active enzyme increased NF phospho-epitopes and increased NF axonal transport. Longer treatment with PD98059 shifted NF transport from anterograde to retrograde. PD98059 did not inhibit overall axonal transport nor compromise overall axonal architecture or composition. The p38 MAP kinase inhibitor SB202190 did not inhibit NF transport whereas the kinase inhibitor olomoucine inhibited both NF and mitochondrial transport. Axonal transport of NFs containing NF-H whose C-terminal region was mutated to mimic extensive phosphorylation was substantially less affected by PD98059 compared to a wild-type construct. These data suggest that p42/44 MAP kinase regulates NF anterograde transport by NF C-terminal phosphorylation. MAP kinase may therefore stabilize developing axons by promoting the accumulation of NFs within growing axonal neurites.

Animals↗
PubMed1993

Fast axonal transport is required for growth cone advance.

Growth cones are capable of advancing despite linkage to a stationary axonal cytoskeleton in chick and murine dorsal root ganglion neurites. Several lines of evidence point to the growth cone as the site of cytoskeletal elongation. Fast axonal transport is probably the means by which cytoskeletal elements or cofactors are rapidly moved through the axon. We report that direct, but reversible, inhibition of fast axonal transport with laser optical tweezers inhibits growth cone motility if cytoskeletal attachment to the cell body is maintained. Advancement ceases after a distance-dependent lag period which correlates with the rate of fast axonal transport. But severing the axonal cytoskeleton with the laser tweezers allows growth cones to advance considerably further. We suggest that axon elongation requires fast axonal transport but growth cone motility does not.

Animals↗
PubMed2000

Prostaglandin E(2) enhances axonal transport and neuritogenesis in cultured mouse dorsal root ganglion neurons.

The effects of prostaglandin E(2) on axonal transport in cultured mouse dorsal root ganglion neurons were investigated by analysing the number of axonally transported particles under video-enhanced microscopy. Application of prostaglandin E(2) increased the number of particles transported in anterograde and retrograde directions. The EP(2) prostaglandin receptor agonist butaprost mimicked the effect of prostaglandin E(2), but the EP(1)/EP(3) prostaglandin receptor agonist 17-phenyl trinor prostaglandin E(2) and the EP(3) prostaglandin receptor agonist M&B 28767 had no effect. The membrane-permeable cyclic AMP analogue dibutyryl cyclic AMP and the adenylate cyclase activator forskolin mimicked the effect of prostaglandin E(2). The protein kinase A inhibitor H-89 reversibly reduced the number of particles in both anterograde and retrograde directions. The effects of prostaglandin E(2) and dibutyryl cyclic AMP were blocked by H-89. Taken together with previous biochemical studies showing that prostaglandin E(2) increases cyclic AMP levels, the present results suggest that prostaglandin E(2) enhances axonal transport via the EP(2) receptor and cyclic AMP-dependent protein kinase A pathway. We further investigated the role of prostaglandin E(2) in neurite growth. Prostaglandin E(2) increased both the number of cells exhibiting neurites and the neurite growth rate, operating by a similar mechanism to stimulation of axonal transport. Prostaglandin E(2) may modulate axonal transport to supply materials for morphogenesis as well as other functions in sensory neurons.

Animals↗
PubMed1984

Fast axonal transport in central nervous system and peripheral nervous system axons following axotomy.

After axotomy, changes in the composition of fast axonally transported proteins ( FTP ) within the peripheral nervous system (PNS) axons have been reported. The most significant and reproducible changes involved polypeptides found within the molecular weight range of 31.0 to 14.5 kilodaltons ( Bisby , 1980). We wished to determine whether similar changes following axotomy occur in axons of the central nervous system (CNS). Intracranial axotomy of the left optic tract was performed stereotaxically in rats. Six days post axotomy 50 muCi 35[S]-methionine was injected into the vitreous body of both eyes. FTP were isolated within the optic nerves 2 h after isotope injection. The nerve segments were processed for SDS-PAGE, fluorography, and compared to similarly prepared fluorographs of normal and eight day post-axotomy sciatic nerve segments. The labelling of 5 major polypeptide bands (S1, MW congruent to 28,000; S2a , MW congruent to 25,000; S2b , MW congruent to 23,000; T1, MW congruent to 20,200; and T2, MW congruent to 17,000) was studied by laser densitometry. Band S2b showed a highly significant (p less than 0.001) increase in concentration, while bands S1 and T1 demonstrated highly significant decreases in concentration following axotomy of the sciatic nerve. In contrast, after axotomy of the retinal ganglion cell axons the only significant change was a decrease (p less than 0.05) in T1. We suggest that failure of CNS axons to respond similarly to PNS axons following axotomy may be related to the failure of CNS axons to regenerate.

Animals↗
PubMedDate not supplied

[The demonstration of recurrent motor axon collaterals in the chick embryo by using horseradish peroxidase axonal transport].

Motoneurons were labelled by retrograde axonal transport of HRP applied to transected spinal nerves in 9-11-day chick embryos in the in vitro spinal cord preparation. Recurrent motor axon collaterals were revealed in 17 of 48 motor axons which could be followed in the edge regions of labelled motoneuronal pools. The results, coupled with author's earlier electrophysiological data, provide further evidence for the presence of the Renshaw inhibition in the avian spinal cord.

Animals↗
PubMed1991

Pertussis toxin-sensitive G proteins are transported toward synaptic terminals by fast axonal transport.

We find that half of the pertussis toxin-sensitive guanine nucleotide-binding protein (G protein) in the squid (Loligo pealei) giant axon is cytoplasmic and that this species of G protein is intermediate in size between the two forms present in axolemma. This G protein is transported toward synaptic terminals at 44 mm/day. Moreover, these data are consistent with there being two additional steps leading to the maturation of G proteins: (i) association with and transport on intracellular organelles and (ii) modification at the time of transfer to the plasmalemma resulting in a molecular weight shift. Since the other two components of G protein-mediated signal transduction pathways, receptors and effector enzymes, are known to be delivered to the synaptic terminals by fast axonal transport, our findings introduce the possibility that these three macromolecules are assembled as a complex in the cell body and delivered together to the plasma membrane of the axon and synaptic terminals.

Adenosine Diphosphate Ribose↗
PubMed1993

Retardation of fast axonal transport in wobbler mice.

To investigate axonal function in a model of early motor neuron disease, we examined fast and slow components of anterograde axonal transport in the less-affected hindlimb motor neurons of wobbler mice. To study the fast component (FC), we injected tritiated amino acids into the lumbar spinal cord and retrieved the sciatic nerve after 2 or 3 h. The transport distance was the extent of the plateau of labeling; regression analysis indicated that FC was 25% slower in wobbler mice than in unaffected littermates (P < 0.01). To study slow component (SC), [35S]methionine was injected. Transport distances were to the peaks of labeling for structural proteins after 2 or 3 weeks. Rates for each subcomponent (SCa and SCb) were unaffected by wobbler disease. Because the rate of retrograde FC is also unaffected (Mitsumoto et al., Muscle & Nerve 13:121-126, 1990), we conclude that wobbler disease specifically retards anterograde FC in less-affected hindlimb motor neurons, whereas all components of axonal transport are retarded in forelimb motor neurons.

Animals↗
PubMed2003

Alzheimer's presenilin 1 mutations impair kinesin-based axonal transport.

Several lines of evidence indicate that alterations in axonal transport play a critical role in Alzheimer's disease (AD) neuropathology, but the molecular mechanisms that control this process are not understood fully. Recent work indicates that presenilin 1 (PS1) interacts with glycogen synthase kinase 3beta (GSK3beta). In vivo, GSK3beta phosphorylates kinesin light chains (KLC) and causes the release of kinesin-I from membrane-bound organelles (MBOs), leading to a reduction in kinesin-I driven motility (Morfini et al., 2002b). To characterize a potential role for PS1 in the regulation of kinesin-based axonal transport, we used PS1-/- and PS1 knock-inM146V (KIM146V) mice and cultured cells. We show that relative levels of GSK3beta activity were increased in cells either in the presence of mutant PS1 or in the absence of PS1 (PS1-/-). Concomitant with increased GSK3beta activity, relative levels of KLC phosphorylation were increased, and the amount of kinesin-I bound to MBOs was reduced. Consistent with a deficit in kinesin-I-mediated fast axonal transport, densities of synaptophysin- and syntaxin-I-containing vesicles and mitochondria were reduced in neuritic processes of KIM146V hippocampal neurons. Similarly, we found reduced levels of PS1, amyloid precursor protein, and synaptophysin in sciatic nerves of KIM146V mice. Thus PS1 appears to modulate GSK3beta activity and the release of kinesin-I from MBOs at sites of vesicle delivery and membrane insertion. These findings suggest that mutations in PS1 may compromise neuronal function by affecting GSK-3 activity and kinesin-I-based motility.

Alzheimer Disease↗
PubMed1999

The regulation of the retrograde axonal transport of (125)I-beta nerve growth factor is independent of calcium.

Calcium has been shown to play a major role in the regulation of endocytosis and exocytosis of synaptic vesicles and retrograde axonal transport of proteins. The role of calcium in the regulation of neurotrophin retrograde axonal transport is unknown. This study aimed to determine if calcium plays a role in the uptake and retrograde axonal transport of (125)I-beta nerve growth factor ((125)I-betaNGF) within sympathetic neurons innervating the iris by comparing it with (125)I-anti-dopamine beta hydroxylase (anti-DBH). The nonspecific voltage-sensitive calcium channel (VSCC) antagonists, cadmium (200 nmol/eye) and nickel (100 nmol/eye) reduced the amount of (125)I-anti-DBH retrograde axonal transport by 90 and 70%, respectively. In contrast, cadmium (200 nmol/eye) had no effect on (125)I-betaNGF retrograde axonal transport, while nickel (100 nmol/eye) caused a significant increase in the amount transported to the ganglia. The L-type VSCC antagonist nifedipine (10 nmol/eye) and N-type VSCC antagonist omega-conotoxin (1.5 nmol/eye) both had no effect on (125)I-anti-DBH retrograde axonal transport which suggests that these types of calcium channels are not involved in the exocytosis/endocytosis of anti-DBH containing vesicles. Thapsigargin (0.2 nmol/eye), an inhibitor of sarcoplasmic reticulum Ca(2+)-ATPases also significantly inhibited (125)I-anti-DBH transport but had no effect on (125)I-betaNGF retrograde transport. This suggests that (125)I-anti-DBH and (125)I-betaNGF are internalized into different vesicle types and that the endocytosis and retrograde axonal transport of (125)I-betaNGF are not dependent upon calcium.

Animals↗
PubMed2003

Polyglutamines stop traffic: axonal transport as a common target in neurodegenerative diseases.

In this issue of Neuron, two papers provide evidence that polyglutamine (polyQ) proteins disrupt axonal transport. Gunawardena et al. show that normal levels of huntingtin are required for proper axonal transport in Drosophila. In addition, expression of expanded polyQ proteins disrupts axonal transport in larval neurons. Szebenyi and colleagues find that polyQ proteins directly inhibit fast axonal transport using axoplasm from the squid giant axon and suggest that axonal transport defects may be a common feature of polyQ disease pathogenesis.

Animals↗
PubMed2004

Axonal transport of human alpha-synuclein slows with aging but is not affected by familial Parkinson's disease-linked mutations.

Biochemical and genetic abnormalities of alpha-synuclein (alpha-Syn) are implicated in the pathogenesis of Parkinson's disease (PD) and other alpha-synucleinopathies. The abnormal intraneuronal accumulations of alpha-Syn in Lewy bodies (LBs) and Lewy neurites (LNs) have implicated defects in axonal transport of alpha-Syn in the alpha-synucleinopathies. Using human (Hu) alpha-Syn transgenic (Tg) mice, we have examined whether familial PD (FPD)-linked mutations (A30P and A53T) alter axonal transport of Hualpha-Syn. Our studies using peripheral nerves show that Hualpha-Syn and Moalpha-Syn are almost exclusively transported in the slow component (SC) of axonal transport and that the FPD-linked alpha-Syn mutations do not have obvious effects on the axonal transport of alpha-Syn. Moreover, older pre-symptomatic A53T Hualpha-Syn Tg mice do not show gross alterations in the axonal transport of alpha-Syn and other proteins in the SC, indicating that the early stages of alpha-synucleinopathy in A53T alpha-Syn Tg mice are not associated with gross alterations in the slow axonal transport. However, the axonal transport of alpha-Syn slows significantly with aging. Because the rate of axonal transport affects the stability and accumulation of proteins in axons, age-dependent-slowing alpha-Syn is a likely contributor to axonal aggregation of alpha-Syn in alpha-synucleinopathy.

Aging↗
PubMed1993

An in vitro system for the study of slow axonal transport.

Here we present a model system which for the first time permits studies of slow axonal transport in vitro. Axonally transported proteins of rat vagus nerves were radiolabelled with [35S]methionine in the nodose ganglion in vitro and were incubated for up to 3 days in culture medium. Slowly transported proteins were analyzed by one- and two-dimensional polyacrylamide gel electrophoresis and identified on Western blots of two-dimensional gels with antibodies to actin and alpha-tubulin. The system will be valuable for pharmacological analysis of the mechanisms of slow transport.

Animals↗
PubMed1984

Axonal transport of [35S]methionine labeled proteins in Xenopus optic nerve: phases of transport and the effects of nerve crush on protein patterns.

Axonal transport of proteins in the Xenopus optic nerve was examined by labeling proteins in the eye with [35S]methionine injected intraocularly and then analyzing the labeled proteins in the eye, nerve, and tectum on linear gradient SDS polyacrylamide gels at different times after the injection. Because the optic nerve in Xenopus is short, in order to distinguish transported proteins from locally synthesized proteins, the optic nerve on one side of the animal was crushed at the orbit (to stop axonal transport) 5-30 min prior to injection and the crushed and normal nerve segments were compared. Proteins in the intact nerve which were absent in the crushed nerve were identified as axonally transported proteins. By such criteria several waves corresponding to transported material moving at greater than or equal to 6 mm/day, 1.6-2.8 mm/day, and approximately 0.2 mm/day were detected in the nerve. The most rapid phases of transport could be further resolved in the optic tectum into 3 additional components at 60-96 mm/day, 30-48 mm/day, and 6-11 mm/day. Analysis of labeled proteins in the crushed nerves distal to the crush, near the injury site, revealed several locally synthesized proteins (mol. wt. 54,000, 48,000, 43,000 daltons) which were not present in normal, uninjured nerves. Such proteins are probably synthesized by glia in response to injury.

Animals↗
PubMed1999

Axonal transport of activating transcription factor-2 is modulated by nerve growth factor in nociceptive neurons.

The aim of this study was to determine whether axonal transport of activating transcription factor-2 (ATF2) occurs in adult sensory neurons, and whether this process is under neurotrophin control. Antisera to both total ATF2 and to the activated (i.e., phosphorylated) form were used for immunocytochemistry and Western blotting. ATF2 was localized to predominantly nociceptive dorsal root ganglion cells in adult rats and shown to accumulate proximal and distal to a sciatic nerve ligature as a result of axonal transport. Subcutaneous injection of nerve growth factor (NGF) decreased the levels of fast retrograde axonal transport of activated ATF2 by 97% (p < 0.05) and elevated levels of retrograde axonal transport of total ATF2 by twofold (p < 0.02). In contrast, blocking endogenous NGF using an anti-NGF antibody induced an elevation in retrograde axonal transport of activated ATF2 of 4. 5-fold (p < 0.05) and decreased retrograde axonal transport of total ATF2 by 72% (p < 0.05). NGF or anti-NGF treatment had no effect on the anterograde transport levels of total or activated ATF2. This study shows that signaling by target-derived NGF to the cell bodies of sensory neurons consists, in part, of the modulation of levels and activation status of a retrogradely transported transcription factor, ATF2.

Activating Transcription Factor 2↗