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PubMed1982

Functions of retrograde axonal transport.

Retrograde axonal transport conveys materials from axon to cell body. One function of this process is recycling of materials originally transported from cell body to axon. In motoneurons, 50% of fast-transported protein is returned. Reversal probably occurs mainly at nerve terminals and, for labeled proteins, is nonselective. Proteolysis is not required, although changes in tertiary protein structure may occur with a repackaging of molecules in organelles different from those in which they were anterograde-transported. A second function is transfer of information about axonal status and terminal environment. Premature reversal of transport adjacent to an axon injury may be a component of a signal that initiates cell body chromatolysis. Transport of target cell-derived molecules with trophic effects on the cell body is exemplified by nerve growth factor transport in neurons dependent on it, and is probably a widespread phenomenon in the developing nervous system. Disorders in retrograde transport or reversal occur in some experimental neuropathies, and certain viruses, as well as tetanus toxin, may gain access to the central nervous system by this route.

Animals↗
PubMed2001

Neurofilaments consist of distinct populations that can be distinguished by C-terminal phosphorylation, bundling, and axonal transport rate in growing axonal neurites.

We examined the steady-state distribution and axonal transport of neurofilament (NF) subunits within growing axonal neurites of NB2a/d1 cells. Ultrastructural analyses demonstrated a longitudinally oriented "bundle" of closely apposed NFs that was surrounded by more widely spaced individual NFs. NF bundles were recovered during fractionation and could be isolated from individual NFs by sedimentation through sucrose. Immunoreactivity toward the restrictive C-terminal phospho-dependent antibody RT97 was significantly more prominent on bundled than on individual NFs. Microinjected biotinylated NF subunits, GFP-tagged NF subunits expressed after transfection, and radiolabeled endogenous subunits all associated with individual NFs before they associated with bundled NFs. Biotinylated and GFP-tagged NF subunits did not accumulate uniformly along bundled NFs; they initially appeared within the proximal portion of the NF bundle and only subsequently were observed along the entire length of bundled NFs. These findings demonstrate that axonal NFs are not homogeneous but, rather, consist of distinct populations. One of these is characterized by less extensive C-terminal phosphorylation and a relative lack of NF-NF interactions. The other is characterized by more extensive C-terminal NF phosphorylation and increased NF-NF interactions and either undergoes markedly slower axonal transport or does not transport and undergoes turnover via subunit and/or filament exchange with individual NFs. Inhibition of phosphatase activities increased NF-NF interactions within living cells. These findings collectively suggest that C-terminal phosphorylation and NF-NF interactions are responsible for slowing NF axonal transport.

Amoxicillin-Potassium Clavulanate Combination↗
PubMed1989

Selective axonal transport in a single cholinergic axon of Aplysia--role of colchicine-resistant microtubules.

Substance-specific selective axonal transport was examined in a single axon by injecting [3H]leucine and [14C]acetylcholine simultaneously into the cell body of a giant cholinergic neuron (R2) in the abdominal ganglion of Aplysia kurodai. The ganglion and attached nerves were cultured for several hours after the injection and the migration of radioactive substances along the axons of the injected neuron was examined. The substances examined were 3H labeled membrane proteins and soluble proteins synthesized in the cell body, 14C labeled bound acetylcholine formed in the cell, injected [3H]leucine and soluble [14C]acetylcholine. Membrane proteins and bound acetylcholine (plus a part of soluble acetylcholine) moved along the axon somatofugally at maximum velocities of 2.4 and 1.7 mm/h, respectively, at 25 degrees C. Soluble proteins, free leucine and most of the soluble acetylcholine did not move by fast axonal transport but diffused inside the axon of the neuron R2 at rates predicted from their expected diffusion constants in the axoplasm [Koike H. and Nagata Y. (1979) J. Physiol. 295, 397-417]. The diffusion kinetics of these substances were analysed and used for determination of true axon length, and to separate axonal transport components from diffusing components. An antimitotic drug, colchicine, selectively suppressed the axonal transport of membrane proteins but not of acetylcholine at 1-5 mM concentration, though it finally blocked the axonal transport of acetylcholine at 20 mM. When 1-5 mM colchicine was separately perfused only to the distal axon of the neuron R2, the migration of membrane proteins was stopped just proximal to the colchicine perfusion zone but acetylcholine migration was not disturbed by the drug. The moving component of acetylcholine was recovered by sucrose density centrifugation from a compartment previously reported as that of vesicular acetylcholine. As a possible mechanism of this selective axonal transport, it is proposed that there are two groups of microtubules: a colchicine-sensitive group of microtubules which may transport membrane proteins, and a colchicine-resistant group which may preferentially transport the transmitter substance acetylcholine at a slower rate.

Acetylcholine↗
PubMed1983

Axon-myelin transfer of glycerol-labeled lipids and inorganic phosphate during axonal transport.

Axon-to-myelin transfer of lipids precursors have been studied in the rabbit optic system by intraocular injection of [32P]orthophosphate, [14C]glycerol and [3H]glycerol. Choline and ethanolamine phosphoglycerides and myelin showed increasing [32P]-radioactivity between 7 and 21 days following injection, while [3H]- and [14C]-radioactivities remained relative constant. The latter radioactivities decreased, however, in all the axon- and axolemma-enriched fractions during the same period. These findings supported the concept that a portion of substances undergoing axonal transport enters the pool of myelin lipids by two mechanisms: transcellular transfer of intact lipid and axon-myelin transfer of precursors which are re-utilized for lipid biosynthesis by myelin-localized enzymes. The present study shows that inorganic phosphate, possibly generated by catabolic activity within the axon, is able to enter myelin and participate in the re-utilization mechanism as previously described for serine, choline and acyl chains. The relative invariance of the 3H:14C ratio suggested that the majority of glycerol is not re-utilized in this manner but probably enters myelin through transfer of intact lipid. These and earlier results suggest a possible form of metabolic dependence of myelin on tropine substances from the axon.

Animals↗
PubMed1996

Impairment of fast axonal transport in the proximal axons of anterior horn neurons in amyotrophic lateral sclerosis.

We studied the possible impairment of fast axonal transport in patients with amyotrophic lateral sclerosis (ALS) to gain some insight into the pathogenesis of the disease. We carried out an ultrastructural investigation of the proximal axons (axon hillock and initial segment) of the anterior horn neurons on samples from 11 ALS patients; specimens from 12 age-matched individuals who died of nonneurological diseases served as controls. Eighty-seven proximal axons that emanated directly from normal-appearing neurons were examined in each group of subjects. Increased smooth endoplasmic reticulum (SER) and the formation of bundles of fibrillary SER with a single unit membrane were not uncommonly observed in the initial segment of the patients with ALS. In some instances, there was loss of the parallel SER arrangement along the longitudinal axis. When viewed in transverse sections, the bundles had a tubular appearance. These morphologic changes of SER were exclusively demonstrated in patients with ALS. A marked increase or accumulation of mitochondria and lysosomes was more common in the proximal axons, particularly in the axon hillock, of ALS patients than of control subjects. The accumulation of these membrane-bounded cytoplasmic organelles suggests that fast axonal transport is impaired in the proximal axons of individuals with ALS. In addition, there were Lewy body-like hyaline inclusions, lipofuscin granules, and multiple membranous structures in the proximal axons. The presence of these unusual structures may also be a reflection of axonal transport dysfunction. By contrast, in the central chromatolytic neurons, there was not only a decrease in the number of neurofilaments in the axon hillock and initial segment, but also of mitochondria, lysosomes, and SER. In some instances, none of these cytoplasmic organelles was seen. These findings support the notion that the outflow of cytoplasmic constituents from the anterior horn cell body into the proximal axon may be impaired in central chromatolytic neurons.

Aged↗
PubMed2000

Neurofilaments are transported rapidly but intermittently in axons: implications for slow axonal transport.

Slow axonal transport conveys cytoskeletal proteins from cell body to axon tip. This transport provides the axon with the architectural elements that are required to generate and maintain its elongate shape and also generates forces within the axon that are necessary for axon growth and navigation. The mechanisms of cytoskeletal transport in axons are unknown. One hypothesis states that cytoskeletal proteins are transported within the axon as polymers. We tested this hypothesis by visualizing individual cytoskeletal polymers in living axons and determining whether they undergo vectorial movement. We focused on neurofilaments in axons of cultured sympathetic neurons because individual neurofilaments in these axons can be visualized by optical microscopy. Cultured sympathetic neurons were infected with recombinant adenovirus containing a construct encoding a fusion protein combining green fluorescent protein (GFP) with the heavy neurofilament protein subunit (NFH). The chimeric GFP-NFH coassembled with endogenous neurofilaments. Time lapse imaging revealed that individual GFP-NFH-labeled neurofilaments undergo vigorous vectorial transport in the axon in both anterograde and retrograde directions but with a strong anterograde bias. NF transport in both directions exhibited a broad spectrum of rates with averages of approximately 0.6-0.7 microm/sec. However, movement was intermittent, with individual neurofilaments pausing during their transit within the axon. Some NFs either moved or paused for the most of the time they were observed, whereas others were intermediate in behavior. On average, neurofilaments spend at most 20% of the time moving and rest of the time paused. These results establish that the slow axonal transport machinery conveys neurofilaments.

Adrenergic Fibers↗
PubMed2001

High expression and anterograde axonal transport of aminoterminal sonic hedgehog in the adult hamster brain.

Sonic hedgehog (SHH) is considered to play an important role in tissue induction and patterning during development, particularly in determining neuronal cell fate in the ventral neural tube and in the embryonic forebrain. SHH precursor is autoproteolytically cleaved to an aminoterminal fragment (SHHN) which retains all known SHH biological activities. Here, we demonstrate the expression of a 22-kDa SHHN immunoreactive peptide in developing and adult hamster brain regions using a rabbit antiserum directed against a mouse SHHN fragment. Interestingly, SHHN was developmentally regulated with the highest expression observed in the adult brain, was resistant to Triton X-100 solubilization at 4 degrees C and partitioned with the raft component ganglioside GM1 during density gradient centrifugation. In rat brain, Shh transcripts were identified by double in situ hybridization in GABAergic neurons located in various basal forebrain nuclei including globus pallidus, ventral pallidum, medial septum-diagonal band complex, magnocellular preoptic nucleus and in cerebellar Purkinje cells as well as in motoneurons of several cranial nerve nuclei and of the spinal cord. We show that radiolabelled SHHN peptides are synthesized in the adult hamster retina and are transported axonally along the optic nerve to the superior colliculus in vivo. Our data indicate that SHHN is associated with cholesterol rich raft-like microdomains and anterogradely transported in the adult brain, and suggest that the roles of this extracellular protein are more diverse than originally thought.

Age Factors↗
PubMed2006

Direct evidence for coherent low velocity axonal transport of mitochondria.

Axonal growth depends on axonal transport. We report the first global analysis of mitochondrial transport during axonal growth and pauses. In the proximal axon, we found that docked mitochondria attached to the cytoskeletal framework that were stationary relative to the substrate and fast axonal transport fully accounted for mitochondrial transport. In the distal axon, we found both fast mitochondrial transport and a coherent slow transport of the mitochondria docked to the axonal framework (low velocity transport [LVT]). LVT was distinct from previously described transport processes; it was coupled with stretching of the axonal framework and, surprisingly, was independent of growth cone advance. Fast mitochondrial transport decreased and LVT increased in a proximodistal gradient along the axon, but together they generated a constant mitochondrial flux. These findings suggest that the viscoelastic stretching/creep of axons caused by tension exerted by the growth cone, with or without advance, is seen as LVT that is followed by compensatory intercalated addition of new mitochondria by fast axonal transport.

Animals↗
PubMed1981

Axonal transport in the central axon of sensory neurons during regeneration of their peripheral axon.

Following sciatic nerve injury (which provokes prompt regeneration of peripheral sensory axons) there was no change in the ratio between amounts of labeled protein conveyed by fast axonal transport into the central and peripheral axons. A change in composition of the transported protein, characteristic of regenerating peripheral axons, also occurred in the central axons. When the peripheral axon is injured, changes in axonal transport thus affect both processes, and there is no routing of fast-transported protein into or away from the regenerating process.

Animals↗
PubMed1985

Axonal transport of cytoskeletal proteins in aluminum toxicity. Aluminum toxicity and axonal transport.

Aluminum administration in certain species results in the accumulation of neurofilament bundles within the neuronal perikaryon and the proximal neuronal processes. The study presented here was designed to investigate how aluminum exerts its effects on the neuronal cytoskeleton. Microinjections of AlCl3 were administered directly to the rabbit lumbar spinal cord; the injections resulted in the accumulation of neurofilament bundles in upwards of 80% of the anterior horn cells. Approximately 7 d later, [35S]methionine was administered to the same region, and exactly 14 d after the radioactive pulse the animals were sacrificed. Sequential 3-mm segments of the sciatic nerves beginning at the root exit zone were processed for gel electrophoresis and fluorography. The counts incorporated into gel bands representing actin, tubulin, and the neurofilament (NF) subunits were determined for each segment, and a distribution curve for the pooled control and pooled aluminum-treated rabbits was constructed. The distribution curves for the two groups, separately analyzed for each cytoskeletal protein, did not significantly differ using an analysis of variance. We conclude that an interruption of slow axonal transport does not occur in this model of aluminum-induced lumbar myelopathy.

Aluminum↗
PubMed2006

Endothelin-1 impairs retrograde axonal transport and leads to axonal injury in rat optic nerve.

The purpose of this study was to examine the effects of endothelin-1 (ET-1) on retrograde axonal transport in the rat optic nerve. Vehicle or ET-1 (0.2, 1, or 5 pmol/eye) were injected into the vitreous body in Sprague-Dawley rats. Retinal vessels were observed, using a fundus camera, before, and at 10 min, 3 days and 7 days after a single intravitreous injection. Two days after the injection, a neuronal tracer, fluoro gold, was administered via the superior colliculi to retrogradely label active retinal ganglion cells (RGCs). Five days after the tracer administration, retrogradely labeled RGCs were evaluated in the flat-mounted retina, and cross sections from each optic nerve were graded for injury by four independent, masked observers. ET-1 at 5 pmol/eye caused a significant constriction of retinal vessels (versus the vehicle-treated group) at 10 min after the injection. Intravitreous injection of ET-1 caused a dose-related decrease in the number of retrogradely labeled RGCs. Injection of 5 pmol/eye ET-1 led to a statistically significant decrease in the number of retrogradely labeled RGCs (versus the vehicle-treated group). ET-1 at 1 and 5 pmol/eye caused histological optic nerve damage (evaluated using a graded scale). The histological optic nerve damage correlated with the number of retrogradely labeled RGCs. In conclusion, a single intravitreous injection of ET-1 impaired retrograde axonal transport in the rat optic nerve and this impairment correlated with the histological optic nerve damage.

Animals↗
PubMed1988

Progressive deficits in retrograde axon transport precede degeneration of motor axons in acrylamide neuropathy.

Single injection of acrylamide (1.3 mmol/kg, i.p.) inhibited retrograde axon transport of [125I]tetanus toxin in hen sensory and motor axons. Retrograde axon transport deficits appeared within hours of dosing with acrylamide. The inhibitory effect of acrylamide on retrograde axon transport was transient since transport deficits were not detectable 35 h after dosing. Acrylamide impaired the retrograde movement but not the uptake of [125I]tetanus toxin in the axon. Multiple doses of acrylamide (0.42 mmol/kg, i.p.) induced progressive clinical signs of acrylamide neuropathy that correlated with increasing deficits in retrograde axon transport of [125I]tetanus toxin to ventral spinal cord. Deficits were also observed in sensory neurons but were not statistically significant. Accumulated decrements in retrograde axon transport may be the underlying cause of degeneration of motor axons in acrylamide neuropathy in fowl.

Acrylamide↗
PubMed2005

Anterograde axonal transport of the exogenous cellular isoform of prion protein in the chick visual system.

The cellular isoform of endogenous, newly synthesized prion protein (PrPc) can be transported by axons in the anterograde direction. To determine whether a mechanism exists for secreted PrPc to be internalized and then axonally transported, we analyzed internalization and anterograde axonal transport of radiolabeled recombinant PrPc after its intraocular injection in chick embryos. Internalization and axonal transport of exogenous PrPc to the midbrain by retinal ganglion cells (RGCs) is efficient, saturable and likely receptor-mediated. Ultrastructural quantitative localization of radiolabeled PrPc within RGC soma showed significant labeling of vesicular/endosomal compartments and much less labeling present over the Golgi apparatus and lysosomes, which indicates slow degradation of exogenous PrPc in this system. These data show that a mechanism exists to internalize a secreted form of PrPc and then to axonally transport such PrPc in an anterograde direction. This may provide an additional, novel mechanism for prion protein to spread among neurons.

Animals↗
PubMed1986

The kinematics of turnaround and retrograde axonal transport.

Rapid axonal transport of a pulse of 35S-methionine-labelled material was studied in vitro in the sensory neurons of amphibian sciatic nerve using a position-sensitive detector. For 10 nerves studied at 23.0 +/- 0.2 degrees C it was found that a pulse moved in the anterograde direction characterized by front edge, peak, and trailing edge transport rates of (mm/d) 180.8 +/- 2.2 (+/- SEM), 176.6 +/- 2.3, and 153.7 +/- 3.0, respectively. Following its arrival at a distal ligature, a smaller pulse was observed to move in the retrograde direction characterized by front edge and peak transport rates of 158.0 +/- 7.3 and 110.3 +/- 3.5, respectively, indicating that retrograde transport proceeds at a rate of 0.88 +/- 0.04 that of anterograde. The retrograde pulse was observed to disperse at a rate greater than the anterograde. Reversal of radiolabel at the distal ligature began 1.49 +/- 0.15 h following arrival of the first radiolabel. Considerable variation was seen between preparations in the way radiolabel accumulated in the end (ligature) regions of the nerve. Although a retrograde pulse was seen in all preparations, in 7 of 10 preparations there was no evidence of this pulse accumulating within less than 2-3 mm of a proximal ligature; however, accumulation was observed within less than 5 mm in all preparations.

Animals↗
PubMed2000

Neuronal lesioning with axonally transported toxins.

Axonally transported toxins can be used to make selective lesions of the nervous system. Collectively, these techniques are termed 'molecular neurosurgery' because they exploit the surface molecular identity of neurons to selectively destroy specific types of neurons. Suicide transport, is anatomically selective but not type-selective. The most widely used suicide transport agents are the toxic lectins (ricin, volkensin) and the immunotoxin, OX7-saporin. The toxic lectins and saporin are ribosome inactivating proteins that irreversibly inhibit protein synthesis. The toxic lectins have binding subunits but saporin requires a targeting vector to gain entrance into cells. Immunolesioning uses monoclonal anti-neuronal antibodies to deliver saporin selectively into neurons that express a particular target surface antigen. Neuropeptide-saporin conjugates selectively destroy neurons expressing the appropriate peptide receptors. Notable experimental uses of these agents include analysis of the function of the cholinergic basal forebrain (192-saporin) and pain research (anti-DBH-saporin, substance P-saporin). It is likely that more immunolesioning and neuropeptide-toxin conjugates will be developed in the near future.

Animals↗
PubMed1987

Vacor neuropathy: ultrastructural and axonal transport studies.

Distal axonal degeneration has been correlated with abnormalities of fast axonal transport in several toxic neuropathies. We have investigated axonal transport in experimental PNU (N-3-pyridylmethyl-N'-p-nitrophenylurea; Vacor) neuropathy, because of the rapid and synchronous degeneration of many terminal axons after a single dose of PNU. Almost all axon terminals at neuromuscular junctions in hindfoot muscles degenerated by 24 hours after the administration of PNU. Fewer affected axons were found in intramuscular nerve twigs, and fewer still in the posterior tibial nerves. No abnormal myelinated axons were found in the sciatic nerve in the thigh. Fast axonal transport in the sciatic nerve remained normal to the mid-thigh, but a reduced amount of labeled transported material reached the posterior tibial nerve at the ankle (27% reduction). Autoradiography showed that nearly no transported material reached the intramuscular nerves and neuromuscular junctions of the hindfeet. These results suggest that toxic impairment of fast anterograde axonal transport may contribute to the axonal degeneration produced by PNU.

Animals↗
PubMed1995

Orthograde axonal transport studies of projections from the zona incerta and pretectum to the basilar pontine nuclei in the rat.

This study employed orthogradely transported axonal tracers to demonstrate, in the rat, projections that reach the basilar pontine nuclei from the zona incerta or pretectal nuclei. Except for the most rostral levels, all subdivisions of the zona incerta give rise to substantive basilar pontine projections. Although some topographic differences exist among the temination patterns of various subdivisions, no clear somatotopically organized scheme is apparent. Most incertopontine axons descend to the basilar pons in association with fibers of the medial lemniscus or crus cerebri and reach ipsilateral ventral and medial pontine gray regions. A sparse number of terminals are evident in the contralateral medial pontine gray. The anterior pretectal axons also descend with the medial lemniscus and crus cerebri to enter exclusively the ipsilateral basilar pons where they terminate most densely in ventral and medial regions. Dual orthograde labeling experiments indicate that some pretectal terminal fields in the pontine gray are shared with incertopontine projections and with afferents from the dorsal column nuclei. This potential convergence of basilar pontine afferent projections is significant in light of 1) the known somatosensory input to the zona incerta and pretectum and 2), the fractured somatotopy of peripheral cutaneous inputs that arrive in the cerebellar cortex via mossy fibers. The present studies also employed electron microscopy to identify synaptic boutons formed by incerto- and pretectopontine axons, and they proved to be remarkably similar. Each is a medium to small-sized bouton that contains spheroidal synaptic vesicles and forms asymmetric membrane specializations. Most incerto- and pretectopontine boutons participate in glomerular synaptic complexes that include a single, centrally located bouton contacted on its perimeter by several types of dendritic profiles including shafts and spine-like appendages. A relatively small number of labeled boutons of either type contacts single, isolated dendritic elements in the neuropil. Taken together, these findings suggest that some basilar pontine neurons might receive convergent inputs from the zona incerta and pretectum as well as other somatosensory-related systems such as the dorsal column nuclei and sensorimotor cortex.

Animals↗