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PubMed1987

Degeneration of trigeminal ganglion neurons caused by retrograde axonal transport of doxorubicin.

Selective nerve cell degeneration was induced in the trigeminal ganglion of the mouse by injecting doxorubicin (Adriamycin) around intact sensory nerve terminals of the head. The drug apparently reached the neurons by retrograde axonal transport after its uptake in nerve branches. A direct fluorescence microscopic method revealed that the compound accumulated in the neurons. Electronmicroscopy showed degeneration of these cells, beginning in the nucleolus and the nucleus. Doxorubicin injected around sensory nerve terminals appears to be a useful compound for selective destruction of mouse sensory neurons. Retrograde axonal transport of neurotoxic compounds is probably an important pathogenetic mechanism in certain forms of intoxication which give rise to lesions in the nervous system.

Animals↗
PubMed1994

Retrograde axonal transport of neurotensin in rat nigrostriatal dopaminergic neurons. Modulation during ageing and possible physiological role.

Biochemical and anatomical data are reported which demonstrate for the first time the existence of a retrograde axonal transport process for a neuropeptide, neurotensin, in rat brain. Neurotensin receptors are mainly located in the striatum on nerve terminals of the nigrostriatal dopaminergic pathway. Thus, the association of specific neurotensin receptors on a well defined pathway provides an excellent model to investigate the existence of such a process. Two hours after the intrastriatal injection of iodinated neurotensin, radioactivity started to accumulate in the ipsilateral substantia nigra. The levels were maximal during the fourth hour. The appearance of this labelling was prevented by injection of a large excess of unlabelled neurotensin or of neurotensin 8-13, an active neurotensin fragment, but not by neurotensin 1-8 which had no affinity for neurotensin receptors. These results suggest that the appearance of radioactivity in the ipsilateral substantia nigra was dependent on the initial binding of this peptide to its receptors in the striatum. HPLC studies demonstrated that the radioactivity found in the substantia nigra corresponded to intact neurotensin and to degradation products of this peptide. Moreover, it has been shown that this retrograde transport was microtubule-dependent and occurred in dopaminergic nigrostriatal neurons. Light and electron microscopic data confirmed and extended the present results. Four and a half hours after intrastriatal injection of iodinated neurotensin, silver grains were mainly detected in dopaminergic perikarya of the substantia nigra pars compacta. The vast majority were associated with neuronal elements and their localization within cell bodies suggests that retrogradely transported neurotensin may be processed along a variety of intracellular pathways including those mediating recycling in the rough endoplasmic reticulum and degradation in lysosomes. However, the presence of silver grains over the nucleus, as well as the increase in tyrosine-hydroxylase mRNA expression in the ipsilateral substantia nigra 4 hr after intrastriatal injection of neurotensin support the concept that neurotensin alone, or associated with its receptor, might be involved in the regulation of gene expression. Finally, we have demonstrated that in old rats the quantity of retrogradely transported neurotensin was significantly decreased as compared to that observed in young adult rats. This retrograde axonal transport of a neuropeptide may represent, as already suggested for growth factors, an important dynamic process conveying information from nerve terminals to the cell body.

Aging↗
PubMed1977

Rapid axonal transport of tyrosine hydroxylase in rabbit sciatic nerves.

We compared the axonal transport of tyrosine hydroxylase with that of dopamine-beta-hydroxylase by means of an in vitro stop-flow technique. Proximal to a locally cooled nerve region, the activity of both enzymes increased linearly for 3 h. Internal standards of partially purified adrenal enzyme showed that the increased activity of tyrosine hydroxylase was not due to changes in activators or inhibitors. Furthermore, this increased activity represented increased V max, unaccompanied by changes in Km for tyrosine; probably, therefore, it reflected increased concentrations of the enzyme. From the rates of increase of enzyme activity, we calculated that, on the average, tyrosine hydroxylase was transported at 0.78 mm/h, and dopamine-beta-hydroxylase at 2.4 mm/h. Much less tyrosine hydroxylase than dopamine-beta-hydroxylase seemed free to move in the nerves, suggesting greater similarity between true transport velocities than between average velocities of these enzymes. When nerves were rewarmed after local cooling for 3 h, waves of accumulated enzyme activity moved distally. The wave of dopamine-beta-hydroxylase activity had a single peak moving at about 14 mm/h. The wave of tyrosine hydroxylase activity had a small component moving this fast, but more of it moved slower, at velocities down to 5 mm/h...

Animals↗
PubMed1977

Axonal transport in the electromotor nerves of Torpedo marmorata.

Studies on the axonal transport of cholinergic cell components were made on the electromotor nerves of Torpedo marmorata. Choline acetyltransferase was rapidly accumulated at ligatures on Torpedo nerves, both in vivo and in segments incubated in vitro. In vivo accumulation was maximal approximately one month after nerve interruption. Orthograde transport (both in vitro and in vivo) is calculated to have a velocity of 50--140 mm/day, if, as double-ligature experiments suggest, only about 15% of the axoplasmic enzyme is mobile. A small retrograde accumulation of the transferase was demonstrated. Lactate dehydrogenase did not accumulate but a slight reduction of its activity at ligatures was observed. In contrast to mammalian cholinergic nerves, no accumulation of esterase was observed. ACh accumulation proximal to a cut was apparent and may result in part from local synthesis in the presence of elevated levels of its synthesizing enzyme. Measurements have been made on the activity of choline acetyltransferase in the brain and all parts of the "electric system". In view of these results it is difficult to see how the measured rate of axonal translocation is sufficient to supply the levels of the enzyme found within the electric organ. Within the electromotor cells, choline acetyltransferase is highly concentrated in the axon terminals.

Acetylcholine↗
PubMed2005

Disruption of the MAP1B-related protein FUTSCH leads to changes in the neuronal cytoskeleton, axonal transport defects, and progressive neurodegeneration in Drosophila.

The elaboration of neuronal axons and dendrites is dependent on a functional cytoskeleton. Cytoskeletal components have been shown to play a major role in the maintenance of the nervous system through adulthood, and changes in neurofilaments and microtubule-associated proteins (MAPs) have been linked to a variety of neurodegenerative diseases. Here we show that Futsch, the fly homolog of MAP1B, is involved in progressive neurodegeneration. Although Futsch is widely expressed throughout the CNS, degeneration in futsch(olk) primarily occurs in the olfactory system and mushroom bodies. Consistent with the predicted function of Futsch, we find abnormalities in the microtubule network and defects in axonal transport. Degeneration in the adult brain is preceded by learning deficits, revealing a neuronal dysfunction before detectable levels of cell death. Futsch is negatively regulated by the Drosophila Fragile X mental retardation gene, and a mutation in this gene delays the onset of neurodegeneration in futsch(olk). A similar effect is obtained by expression of either fly or bovine tau, suggesting a certain degree of functional redundancy of MAPs. The futsch(olk) mutants exhibit several characteristics of human neurodegenerative diseases, providing an opportunity to study the role of MAPs in progressive neurodegeneration within an experimentally accessible, in vivo model system.

Animals↗
PubMed1984

Is protease activity involved in fast axonal transport?

N-alpha-p-Tosyl-L-Lysine Chloromethyl Ketone (TLCK), a protease inhibitor, was found to irreversibly inhibit rapid axonal transport of protein in vitro in the frog sciatic nerve. TLCK exerted its action at the axonal level and seemed to depress the rate rather than the amount of transported protein. The efficiency of TLCK as a protease inhibitor was demonstrated by polyacrylamide gel electrophoresis, which showed that degradation of high molecular weight proteins (presumably neurofilament subunits) into a 25000 dalton protein could be induced by exposing the frog nerves to triton-X and prevented by the presence of TLCK. Findings that TLCK, at a transport inhibiting concentration (0.1 mM), had little or no effects on either protein synthesis or ATP levels, suggest that TLCK did not affect transport due to general cytotoxic properties. The effects of TLCK is discussed in relation to possible roles of protease activity in axonal transport.

Adenosine Triphosphate↗
PubMed1998

Axonal transport of mutant superoxide dismutase 1 and focal axonal abnormalities in the proximal axons of transgenic mice.

Superoxide dismutase 1 (SOD1), a ubiquitously expressed enzyme, detoxifies superoxide radicals and participates in copper homeostasis. Mutations in this enzyme have been linked to a subset of autosomal dominant cases of familial amyotrophic lateral sclerosis (FALS), a disorder characterized by selective degeneration of motor neurons. Transgenic mice expressing FALS mutant human (Hu) SOD1 at high levels develop a motor neuron disease, indicating that mutant Hu SOD1 gains properties that are particularly toxic to motor neurons. In this report, we demonstrate that transgenic mice expressing Hu SOD1 with the G37R FALS mutation, but not mice expressing wild-type enzyme, develop focal increases in immunoreactivity in the proximal axons of spinal motor neurons. This SOD1 immunoreactivity and immunoreactivity to hypophosphorylated neurofilament H epitopes are found adjacent to small vacuoles in axons. Using metabolic radiolabeling methods, we show that mutant G37R HuSOD1 as well as endogenous mouse SOD1 are transported anterograde in slow component b in motor and sensory axons of the sciatic nerve. Together, these findings suggest that anterogradely transported mutant SOD1 may act locally to damage motor axons.

Animals↗
PubMed1985

Synthesis and fast axonal transport of proteins in the isolated Aplysia nervous system.

Fast axonal transport and neuronal protein synthesis was studied in the isolated nervous system of Aplysia californica. The abdominal ganglion with attached pleural-abdominal connectives (PAC) was removed and the ganglion pulse-labelled with [35S]methionine for 30 min in vitro. The axon containing connectives were ligated 24-28 mm from the ganglia and the system was perfused with chase media for 6-72 h to allow labelled rapidly transported proteins to accumulate at the ligature. One-dimensional polyacrylamide gel electrophoresis (PAGE) and fluorography was used to analyze the distribution of rapidly transported proteins along the right PAC. By 12 h, a significant accumulation of labelled proteins at the ligature was present but the build up was not complete until 48 h when almost no trailing of rapidly transported proteins was observed. Quantitation of the transport profiles of several rapidly transported proteins suggested a discontinuous release of proteins from the cell body. Analysis using two-dimensional PAGE revealed 10 major groups of rapidly transported proteins. These proteins were all identified among the total complement of newly synthesized proteins in cell R2. Not all rapidly transported proteins are cleared from the cell body at the same rate. Several of the major groups were no longer present in the neuron cell body 24 h after labelling, indicating that these species are selectively exported; others were still present after 3 days, suggesting that these proteins with a longer residence time have functions in both somatic and axonal regions of the neuron.

Animals↗
PubMed2000

Obstructed axonal transport of BDNF and its receptor TrkB in experimental glaucoma.

PURPOSE: In both animal model system and in human glaucoma, retinal ganglion cells (RGCs) die by apoptosis. To understand how RGC apoptosis is initiated in these systems, the authors studied RGC neurotrophin transport in experimental glaucoma using acute intraocular pressure (IOP) elevations in rats and chronic IOP elevation and unilateral optic nerve transections in monkeys. METHODS: Eyes were studied in masked fashion by light and electron microscopy and by immunohistochemistry with antibodies directed against the tyrosine kinase receptors (TrkA, B, and C) and against brain-derived neurotrophic factor (BDNF), as well as by autoradiography to identify retrograde axonal transport of 125I-BDNF injected into the superior colliculus. RESULTS: With acute glaucoma in the rat, RGC axons became abnormally dilated, accumulating vesicles presumed to be moving in axonal transport at the optic nerve head. Label for TrkB, but not TrkA, was relatively increased at and behind the optic nerve head with IOP elevation. Abnormal, focal labeling for TrkB and BDNF was identified in axons of monkey optic nerve heads with chronic glaucoma. With acute IOP elevation in rats, radiolabeled BDNF arrived at cells in the RGC layer at less than half the level of control eyes. CONCLUSIONS: Interruption of BDNF retrograde transport and accumulation of TrkB at the optic nerve head in acute and chronic glaucoma models suggest a role for neurotrophin deprivation in the pathogenesis of RGC death in glaucoma.

Acute Disease↗
PubMed1986

Axonal transport of substance P-hydrolyzing peptidase in rat sciatic nerves.

The axonal transport of substance P-hydrolyzing peptidase was studied both 2 and 10 days after the ligation of rat sciatic nerves. A peptidase(s) hydrolyzing substance P at the bonds of Phe7-Phe8 and Phe8-Gly9 was found to have accumulated to about 2 times the normal amount in the proximal segment 10 days after ligation. This enzyme activity was inhibited by ethylenediamine tetraacetate or dithiothreitol. These results suggest that this is a metalloendopeptidase which is slowly transported to inactivate neuropeptides in the nerve terminals.

Animals↗
PubMed2003

The kinesin-associated protein UNC-76 is required for axonal transport in the Drosophila nervous system.

Kinesin-I is essential for the transport of membrane-bound organelles in neural and nonneural cells. However, the means by which kinesin interacts with its intracellular cargoes, and the means by which kinesin-cargo interactions are regulated in response to cellular transport requirements are not fully understood. The C terminus of the Drosophila kinesin heavy chain (KHC) was used in a two-hybrid screen of a Drosophila cDNA library to identify proteins that bind specifically to the kinesin tail domain. UNC-76 is an evolutionarily conserved cytosolic protein that binds to the tail domain of KHC in two-hybrid and copurification assays, indicating that kinesin and UNC-76 form a stable complex in vivo. Loss of Drosophila Unc-76 function results in locomotion and axonal transport defects reminiscent of the phenotypes observed in kinesin mutants, suggesting that UNC-76 is required for kinesin-dependent axonal transport. Unc-76 exhibits dosage-sensitive genetic relationships with Khc and Kinesin light chain mutations, further supporting the hypothesis that UNC-76 and kinesin-I work in a common transport pathway. Given the interaction of FEZ1, the mammalian homolog of UNC-76, with protein kinase Czeta, and the role of FEZ1 in axon outgrowth, we propose that UNC-76 helps integrate kinesin activity in response to transport requirements in axons.

Amino Acid Sequence↗
PubMed1979

Fast axonal transport in rat sciatic nerve. Inhibition by pineal indoles.

The effect of pineal indoles on fast axoplasmic transport of proteins in the sciatic nerve was examined in rats injected with [3H]leucine in the sixth lumbar dorsal root ganglion. Melatonin (350-1100 nmol) applied locally in the sciatic nerve impaired significantly axonal transport. At a 350-nmol dose all other indoles tested (i.e., 5-hydroxyindoleacetic acid, 5-methoxyindoleacetic acid, serotonin, N-acetylserotonin, tryptamine, 5-methoxytryptamine) were less potent than melatonin to impair fast axonal flow. Vinblastine injected either into the ganglion or in the sciatic nerve markedly inhibited axonal transport.

5-Methoxytryptamine↗
PubMed1999

Axonal transport of synucleins is mediated by all rate components.

Synucleins are abundant nerve terminal proteins of hitherto unknown function. In diseases with Lewy bodies, human alpha-synuclein concentrates in these lesions in the cell body and mutations in alpha-synuclein lead to heritable Parkinson's disease with Lewy bodies. This indicates that changes in the normal metabolism and axonal transport of alpha-synuclein is perturbed in these diseases. To investigate the normal axonal transport of synucleins we studied the rat visual system by nerve crush operations and metabolic labelling of the retinal ganglion cells followed by immunoprecipitation of nerve segments. We found by immunofluorescence microscopy of the crush-operated nerves that synucleins are transported by fast antero- and retrograde transport and colocalize with synaptophysin and SNAP-25 around the lesion. The metabolic labelling studies demonstrated that synucleins were moved through the nerve with all the rate components, the fast component and the slow components a and b, with component b predominating. Two-dimensional gel electrophoresis revealed that both alpha- and beta-synuclein migrate through the nerve by slow component b in a ratio of 2:1.

Animals↗
PubMed2002

Slow axonal transport: fast motors in the slow lane.

The bulk of neuronally synthesized proteins destined for the axon is transported in a phase of transport approximately 100 times slower (1mm/day) than the vesicular traffic of fast axonal transport (100mm/day). Of late, a number of studies have shed considerable light on the controversies and mechanisms surrounding this slow phase of axonal transport. Along-standing controversy has centered on the form of the transported proteins. One major transport cargo, neurofilament protein, has now been seen in a number of contexts to be transported primarily in a polymeric form, whereas a second cargo tubulin is transported as a small oligomer. The development of techniques to visualize the slow transport process in live cells has demonstrated that instantaneous motions of transported neurofilaments, and presumably other slow transport cargoes, are fast, bidirectional and interspersed with long pauses. This and additional biochemical efforts indicate that traditional fast motors, such as conventional kinesin and dynein, are responsible for these fast motions.

Animals↗
PubMed1990

Basic fibroblast growth factor: receptor-mediated internalization, metabolism, and anterograde axonal transport in retinal ganglion cells.

Basic fibroblast growth factor (bFGF) was radiolabeled and used in axonal transport studies to determine whether certain neuronal populations express functional receptors for bFGF. Unlike 125I-NGF, 125I-bFGF was not retrogradely transported in the adult rat sciatic nerve or from iris to trigeminal ganglion or superior cervical ganglion. However, after intraocular injection of 125I-bFGF into the posterior chamber of the eye of adult rats, radioactivity was detected within the retinal ganglion cell projections. This radioactivity was localized to the ipsilateral optic nerve and in the contralateral lateral geniculate body and the contralateral superior colliculus by using autoradiographic techniques. Direct measurement of the radioactivity in dissected brain regions was used to study the process of 125I-bFGF uptake and transport by retinal ganglion cells. The uptake and transport were specific for biologically active bFGF since neither denatured, biologically inactive 125I-bFGF nor 125I-NGF was taken up and transported. The uptake and transport of 125I-bFGF were saturable phenomena since they were blocked in the presence of excess, unlabeled bFGF. Wheat germ agglutinin, but not heparinase, blocked uptake and transport of 125I-bFGF, a finding that is consistent with the uptake being mediated by high-affinity bFGF receptors. Radioactivity from 125I-bFGF was transported in retinal ganglion cell axons in an anterograde direction at a maximum rate in excess of 1.7 mm/hr. No specific retrograde transport of bFGF to the retina was detected after 125I-bFGF was injected into the superior colliculus. The radioactivity from 125I-bFGF that accumulated in the superior colliculus was lost from this tissue with a half-life of about 22 hr. Autoradiography of proteins separated by SDS-PAGE demonstrated that 125I-bFGF was not substantially degraded in the retina after internalization within retinal ganglion cells. During anterograde transport, however, 125I-bFGF underwent limited proteolytic cleavage resulting in 3 prominent 125I-bFGF derivatives of molecular weights greater than 7000 Da. Although these were the major radioactive species recovered from the superior colliculus after intraocular injection, some intact 125I-bFGF was also detected within the innervated target. These results indicate that retinal ganglion cells express high-affinity receptors for bFGF, that these receptors mediate the internalization of bFGF, that internalized bFGF undergoes limited proteolytic cleavage, and that bFGF and its derivatives are anterogradely transported to the lateral geniculate body and the superior colliculus. These data raise the possibility that bFGF or its derivatives may act as an anterograde trophic factor in the visual system, a system that is known to undergo anterograde transneuronal cell death.

Animals↗
PubMed1990

Axonal transport of substance P-like immunoreactivity in ganglioside-treated diabetic rats.

This study examined the effect of treatment of control and streptozotocin-diabetic rats with a mixture of gangliosides, derived from bovine brain, on parameters of axonal transport of substance P-like immunoreactivity (SPLI) and its levels in sciatic nerve and lumbar spinal ganglia. Rats were treated daily (10 mg/kg i.p.) for 28 days and compared with untreated control and diabetic groups. The duration of diabetes was 28 days in both cases. Untreated diabetic rats showed deficits in accumulation of axonally transported SPLI proximal (59% of controls) and distal (34% of controls) to sciatic nerve ligations (left in place for 12 h). Rates of accumulation were unaltered by diabetes. There were small numerical reductions in the SPLI content of unconstricted sciatic nerve and of L4 and L5 dorsal root ganglia in diabetic rats. None of these diabetes-associated changes was altered by ganglioside treatment, nor was there any indication of an effect of gangliosides on substance P in non-diabetic rats. The implications are discussed in relation to the possible pathogenesis of diabetic neuropathy.

Animals↗
PubMed1988

Calcitonin gene-related peptide in visceral afferent nerve fibres: quantification by radioimmunoassay and determination of axonal transport rates.

An antibody specific for the C-terminus of rat alpha calcitonin gene-related peptide has been used in radioimmunoassay to measure concentrations of immunoreactive peptide in the upper gastrointestinal tract of capsaicin-treated and coeliac ganglionectomized rats, and to measure axonal transport velocities in the vagus and splanchnic nerves. In adult rats that had been treated soon after birth with capsaicin, immunoreactive calcitonin gene-related peptide in the stomach and duodenum was undetectable (less than 0.1 pmol/g) compared with 4-10 pmol/g in control rats. Removal of the coeliac ganglion also reduced concentrations of immunoreactive calcitonin gene-related peptide by 5-fold, but Leu-enkephalin and Met-enkephalin Arg6Gly7Leu8-immunoreactivities (which are thought to occur in intrinsic gut neurons) were unchanged by coeliac ganglionectomy. Concentrations of calcitonin gene-related peptide immunoreactivity in coeliac ganglia were depressed by 90% in capsaicin-treated rats but concentrations of opioid peptide immunoreactivity were similar to control. The results suggest calcitonin gene-related peptide-immunoreactivity in the upper gastrointestinal tract in the rat is predominantly of extrinsic afferent origin. Chromatographic separation on Sephadex G50, or high-performance liquid chromatography revealed that the major immunoreactive form in stomach extracts corresponded to intact calcitonin gene-related peptide, although there was evidence of smaller, less hydrophobic C-terminal fragments. Direct evidence of transport of calcitonin gene-related peptide toward the gut was obtained by ligation of the cervical vagus and greater splanchnic nerves. There was accumulation on the central side of ligatures, which suggested axonal transport velocities in the vagus of about 1.5 mm/h and 0.7 mm/h in splanchnic nerves.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Topographically organized projections from the nucleus subceruleus to the hypoglossal nucleus in the rat: a light and electron microscopic study with complementary axonal transport techniques.

Projections from the nucleus subceruleus (nSC) to the hypoglossal nucleus (XII) were investigated with complementary retrograde and anterograde axonal transport techniques at the light and electron microscopic level in the rat. Injections of WGA-HRP into XII resulted in labeling of neurons in and around the nSC. Labeled nSC neurons were few in number (less than 4 per 40-60 microns sections) and variable in size and shape. Most labeled nSC neurons were medium-sized (mean = 16.89 microns), fusiform, triangular, or oval, with 3-4 dendrites typically oriented dorsomedially and ventrolaterally. These neurons were found throughout the rostrocaudal extent of the nSC but were most numerous medial, dorsomedial, and ventromedial to the motor trigeminal nucleus. Others were observed rostral to the motor trigeminal nucleus and ventral to the parabrachial nuclear complex. Confirmation of retrograde results was obtained following injections of tritiated amino acids or WGA-HRP into the nSC. This resulted in labeling throughout the rostrocaudal extent of XII mainly ipsilaterally. Labeled fibers descended the brainstem in the dorsolateral and, to a lesser extent, in the ventromedial component of Probst's tract. Fibers entered XII mainly rostrally along the lateral border of the nucleus. All regions of XII were recipients of nSC afferents, but the caudoventromedial quadrant contained the greatest density of terminal labeling. Electron microscopic evaluation confirmed that nSC afferents synapsed on motoneurons in XII. Axon terminals containing WGA-HRP reaction product were found contacting dendrites and somata, but primarily the former (81.3% versus 10.6%). Axodendritic terminals synapsed mainly on medium-to-small sized dendrites (less than 3 microns in diameter). The majority of labeled axodendritic terminals (90.1%) contained small, round, and clear synaptic vesicles (S-type: 20-50 nm) and were associated with an asymmetric (60.6%), symmetric (11.4%), or no (18%) postsynaptic specialization. By contrast, most axosomatic terminals contained flattened vesicles (F-type) and formed a symmetric or no postsynaptic specialization (75%). Large dense core vesicles (55-90 nm) were observed within a small proportion of all labeled axon terminals (1.3%). The results from this study demonstrate that the nSC projects to XII, preferentially targets a specific subgrouping of protrusor motoneurons, and synapses on both somata and dendrites, although mainly on the latter. The implications of these data are discussed relative to tongue control.

Afferent Pathways↗