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PubMed1996

Kinesin mutations cause motor neuron disease phenotypes by disrupting fast axonal transport in Drosophila.

Previous work has shown that mutation of the gene that encodes the microtubule motor subunit kinesin heavy chain (Khc) in Drosophila inhibits neuronal sodium channel activity, action potentials and neurotransmitter secretion. These physiological defects cause progressive distal paralysis in larvae. To identify the cellular defects that cause these phenotypes, larval nerves were studied by light and electron microscopy. The axons of Khc mutants develop dramatic focal swellings along their lengths. The swellings are packed with fast axonal transport cargoes including vesicles, synaptic membrane proteins, mitochondria and prelysosomal organelles, but not with slow axonal transport cargoes such as cytoskeletal elements. Khc mutations also impair the development of larval motor axon terminals, causing dystrophic morphology and marked reductions in synaptic bouton numbers. These observations suggest that as the concentration of maternally provided wild-type KHC decreases, axonal organelles transported by kinesin periodically stall. This causes organelle jams that disrupt retrograde as well as anterograde fast axonal transport, leading to defective action potentials, dystrophic terminals, reduced transmitter secretion and progressive distal paralysis. These phenotypes parallel the pathologies of some vertebrate motor neuron diseases, including some forms of amyotrophic lateral sclerosis (ALS), and suggest that impaired fast axonal transport is a key element in these diseases.

Animals↗
PubMed1990

Automatic quantification of fast axonal transport in neuronal cell cultures.

A method is presented which allows the automatic quantification of the fast axonal transport of endogenous organelles in neurites of cultured neuronal cells. Stretches of videotape recordings from Allen video enhanced contrast (AVEC) microscopy are digitized by currently available image processor hardware and analysed off-line on a MicroVAX II. Movements along the axon are calculated in great detail, allowing statistically significant changes to be detected. Interaction from the operator is minimised, thereby bypassing tedious manual analysis. This paper further reports the application of this system to the effect of vanadate treatment on axonal transport in cultures of rat embryonic hippocampal neurons.

Animals↗
PubMed1988

Stable and metastable cytoskeletal polymers carried by slow axonal transport.

The proteins carried by the slow axonal transport in the rat sciatic motor axons were radiolabeled by injecting 35S-methionine into the spinal cord, and the distribution of their solubility through the 2 main components of slow transport (SCa and SCb) was considered. For this purpose, a cytoskeleton-stabilizing buffer was designed in which a pellet enriched in macromolecular and polymeric structures was separated from the solubilized proteins. The monomer/polymer ratios for tubulin were quantified in the 2 rate components. Our results indicate that 90% of the total tubulin was carried with SCa. Of this, 75% was in a polymeric state, versus only 50% of the tubulin carried with SCb. The monomeric tubulin recovered in the soluble fraction was concomitantly transported with the polymerized microtubules, suggesting that it might represent metastable regions of these microtubules. The insoluble and soluble fractions of the transported actin were measured. Actin was mostly (70%) transported with SCb. Of this, more than 80% was recovered in the soluble fraction, but we cannot say whether it was in a monomeric or polymeric state, nor if it was transported free or bound to a structure solubilized during fractionation. The other 30% of the actin, most of it transported with SCa, was recovered in the polymer-enriched fraction, probably bound to a stabilized polymer, such as the microtubules.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Cytoplasmic dynein subunit heterogeneity: implications for axonal transport.

The formation and maintenance of neuronal synapses is dependent on the active transport of material between the cell body and the axon terminal. Cytoplasmic dynein is one motor for microtubule-based axonal transport. Two pools of cytoplasmic dynein have been identified in the axon. They are distinguished by their intermediate and light intermediate chain subunits. Each pool is transported at different rates down the axon in association with different proteins or organelles. This review presents several models to discuss the potential functional roles of these different pools of cytoplasmic dynein during axonal transport.

Animals↗
PubMed2002

Axonal transport, tau protein, and neurodegeneration in Alzheimer's disease.

The molecular causes and the genetic and environmental modifying factors of the sporadic form of Alzheimer's disease (AD) remain elusive. Extrapolating from the known mutations that cause the rare familial forms and from the typical post-mortem pathological lesions in all AD patients--e.g., amyloid plaques and neurofibrillary tangles (NFTs)-the evident molecular candidates are amyloid precursor protein (APP), presenilin, and tau protein. To include ApoE4 as the only certain genetic modifier known leaves us to face the challenge of implementing these very different molecules into an evident pathological partnership. In more than one respect, the proposition of disturbed axonal transport appears attractive with more details becoming available on APP processing and microtubular transport and also of the pathology in the model systems--e.g., transgenic mice expressing APP or protein tau. Conversely, the resistance of APP-transgenic mice with full-blown amyloid pathology to also develop tau-related neurofibrillar pathology is a major challenge for this hypothesis. From the most relevant data discussed here, we conclude that the postulate of disturbed axonal transport as the primary event in AD is difficult to defend. On the other hand, failing axonal transport appears to be of major importance in the later stages in AD, by further compromising tau protein, APP metabolism, and synaptic functioning. Protein tau may thus be the central "executer" in the chain of events leading from amyloid neurotoxicity to tau hyperphosphorylation, microtubular destabilization, disturbed axonal transport, and synaptic failure to neurodegeneration. In order to identify normal physiological processes and novel pathological targets, definition is needed--in molecular detail--of the complex mechanisms involved.

Alzheimer Disease↗
PubMed1988

Axonal transport of opiate receptor subtypes.

The axonal transport of mu and delta receptors in the rat was examined by autoradiography in three fiber systems: vagus nerve, fasciculus retroflexus and corpus callosum. Following ligature or knife cut, sections were incubated with [125I]D-Ala2-MePhe4-Met(O)5-ol-enkephalin to label mu receptors or [125I]D-Ala2-D-Leu5-enkephalin in the presence of 30 nM oxymorphone to selectively label delta receptors. Ligature of the vagus and knife cut of the fasciculus retroflexus produced a time-dependent proximal build-up of mu receptors indicating anterograde axonal flow. In contrast, the corpus callosum has delta but not mu receptors, and these could not be demonstrated to undergo axonal flow. The results suggest that in the fiber tracts examined, mu but not delta opiate receptor subtypes are anterogradely transported toward nerve terminals where they may be inserted in presynaptic membranes.

Animals↗
PubMed1993

Inhibition of kinesin synthesis and rapid anterograde axonal transport in vivo by an antisense oligonucleotide.

Synthetic antisense oligonucleotides have been used to inhibit specific protein synthesis in vivo. Antisense oligonucleotides directed to kinesin heavy chain were injected into the vitreous of anesthetized rabbits in order to assess the effects on transport in the retinal ganglion cells whose axons form the optic nerve. The antisense oligonucleotide specifically inhibited retinal kinesin synthesis by 82 +/- 7% (n = 4). The rapid axonal transport of the membrane proteins into the optic nerve was concomitantly inhibited by 70 +/- 10% (n = 4). These results provide direct evidence for the specific role of kinesin in rapid anterograde transport in vivo and indicate the utility of antisense oligonucleotides to explore neuronal dynamics in a specific neuronal cell type in a living animal.

Animals↗
PubMedDate not supplied

No effect of growth hormone treatment on axonal transport of slow component a in diabetic and nondiabetic rats.

A decreased axonal transport of slow component a (SCa), i.e., neurofilaments, is an early event in experimental diabetes as well as hypothyroidism, and common to these metabolic derangements are decreased levels of serum insulin-like growth factor I (IGF-I). To evaluate the possible connection between these facts, we investigated the effect of growth hormone (GH), which stimulates IGF-I production, on axonal transport of SCa in diabetic and nondiabetic rats. Serum concentrations of IGF-I fell from about 1500 micrograms/L in controls to about 600 micrograms/L in diabetics. GH treatment (100 mu/rat twice daily) normalized IGF-I for the first week of diabetes, after which the level decreased to the level of the untreated diabetics. The SCa transport velocity was found to be decreased in the diabetic nerves as previously reported [0.91 +/- 0.07 = mm/day, n = 9; (mean +/- SD) versus 1.01 +/- 0.09 mm/day, n = 8, in controls, 2 p less than 0.05). No changes were seen for the GH-treated groups (1.03 +/- 0.06 mm/day, (n = 11) in GH-treated controls). The lack of effect of GH treatment can be due to blockage of IGF-I synthesis or the decreased level of thyroid hormone, triiodothyronine (T3), in the diabetic rats.

Analysis of Variance↗
PubMed1988

Lack of evidence for axonal transport of D1 and D2 receptors in the nigro-striatal pathway of the rat.

The possibility that D1 and D2 dopamine receptors are axonally transported in the nigro-striatal pathway has been investigated in the rat by placing a coronal knife cut (sparing the striato-nigral pathway) through the medial forebrain bundle (MFB) and autoradiographically examining the density of D2 (as labeled by [3H]spiperone in the presence of ketanserin) and D1 (as labeled by [3H]SCH 23390) receptors. The efficacy of MFB transection has been assessed by measuring in parallel the binding of [3]ketanserin, a ligand that has been reported to be axonally transported in this bundle. At 12 h post-transection, there was a minor accumulation of [3H]spiperone binding on both sides of the transection. However, (+)butaclamol (1 microM) failed to displace the ligand build-up at the knife cut, thus demonstrating the nonspecific nature of [3H]spiperone accumulation. Similar results were observed at 24, 48, and 72 h after severing the MFB. MFB transection also failed to cause changes in specific [3H]SCH 23390 binding at the knife cut at 12-72 h post-surgery. In contrast, a dramatic accumulation of [3H]ketanserin binding sites was observed rostral and caudal to the cut at 12 h post-transection, attesting to the efficacy of the lesion. These results confirm the existence of both anterograde and retrograde transport of [3H]ketanserin binding sites and suggest that D1 and D2 receptors are not axonally transported in fibers of the nigro-striatal pathway.

Animals↗
PubMed2001

Inhibitory effect of aluminium on the axonal transport of HRP microinjected into dorsal root ganglion neurons in vitro.

In the present study the function of axonal transport in individual neurons under aluminium intoxication was investigated experimentally in comparison with controls. We used the technique of microinjection of horseradish peroxidase (HRP) in dissociated dorsal root ganglia (DRG) neurons and neurons of explant cultures of DRG. Different exposure periods (1 and 6 hours as well as 6 and 10 days) to aluminium were analysed quantitatively. This analysis revealed an impaired anterograde transport of HRP already after a short aluminium intoxication period of only 1 hour in DRG cells in vitro, an effect that increased with a prolonged aluminium exposure for up to 10 days. Hence, functional alterations of the anterograde transport caused by aluminium could be detected even after short exposure periods. Furthermore, the effects of aluminium on anterograde transport mechanisms were reversible 8 days after removal of aluminium. To determine how aluminium affects the cytoskeleton, we performed immunohistochemistry and electron microscopy on cultured DRG neurons. Distinct morphological alterations of the cytoskeleton, especially the accumulation of phosphorylated neurofilaments, appeared after 6 days of aluminium exposure. Our results suggest that neurofilaments are indispensable to the functional integrity of the cytoskeleton and its ability to mediate microtubule-based axonal transport processes.

Aluminum↗
PubMed1983

Blockage of axonal transport in optic nerve induced by elevation of intraocular pressure. Effect of arterial hypertension induced by angiotensin I.

Previous studies have shown that elevation of intraocular pressure blocks rapid axonal transport at the lamina cribrosa of the optic nerve. In this study, IOP-induced blockage of axonal transport was greater in cats with elevation of BP induced by angiotensin I than in control animals with normal BP. The fact that cardiovascular factors influenced IOP-induced blockage of axonal transport suggests that it is due to ischemia; if the blockage were a direct mechanical effect of the IOP on the axons, it should be unaffected by BP. The data also suggest that the vasoconstrictive properties of angiotensin I reduced the ability of the vasculature of the optic nerve head to autoregulate when challenged by elevation of IOP.

Angiotensin I↗
PubMed1994

IL-1 beta-like Freund's adjuvant enhances axonal transport of opiate receptors in sensory neurons.

Chronic pain and inflammation increase substance P in sensory fibres of peripheral nerves in which opiate receptors are known to undergo axonal transport. The aim of the present study was to evaluate a possible modulation of axonal transport of opiate receptors in peripheral nerves during inflammation. After intraplantar injection of Freund's adjuvant to rats, the accumulation of mu and kappa opiate receptors increased on both sides of ligature in sciatic nerves of the injected paw. The contralateral side was unaffected and may serve as control. When IL-1 beta was injected into rat paws, the axonal transport of opiate receptors was increased in a similar way. This suggests that IL-1 beta represents a major mediator to sensitize nociceptors during inflammation through a process requiring retrograde signals.

Animals↗
PubMed1985

Altered axonal transport of cytoskeletal proteins in the mutant diabetic mouse.

Polypeptides in the motor axons of the sciatic nerve in 120-day-old normal and diabetic mice C57BL/Ks (db/db) were labeled by injection of [35S]methionine into the ventral horn of the spinal cord. At 8, 15, and 25 days after the injection, the distribution of radiolabeled polypeptides along the sciatic nerve was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Four major radiolabeled polypeptides, tentatively identified as actin, tubulin, and the two lightest subunits of the neurofilament triplet, were studied in both diabetic and control mice. In the diabetic animals, the two polypeptides identified as actin and tubulin showed a reduction of average velocity of migration along the sciatic nerve, resulting in a higher fraction of radioactivity in the proximal part of the sciatic nerve, whereas the front of radioactivity (advancing at maximal velocity) moved at a normal rate. In contrast, both the average and maximal velocities of the two neurofilament subunits were slower in the diabetic mice than in the control mice. These results indicate that the axonal transport of the cytoskeletal proteins is differentially affected in the course of diabetic neuropathy, and may suggest that the impairment concerns mainly the proteins carried by the slowest component of axonal transport.

Actins↗
PubMed1993

Mechanism of axonal transport. Identification of new molecular motors and regulations of transports.

New molecular motors associated with microtubules and actin have been uncovered very recently. Furthermore, studies of the mechanisms of bidirectional fast axonal transports have clarified new aspects of these processes, such as identification of a kinesin binding protein (kinectin) and regulation of kinesin dissociation from membranous organelles by phosphorylation. These will lead to a more precise understanding of the mechanisms of axonal transports. Concerning the mechanism of the slow transport of cytoskeletal proteins, new approaches have provided further evidence that the axonal cytoskeleton in mammalian systems is largely stationary while dynamic exchanges occur between polymer and a small pool of moving subunits.

Animals↗
PubMed1975

Ionic requirements for rapid axonal transport in vitro in frog sciatic nerves.

The effects of K+, Na+, hypo- and hypertonicity on the synthesis and fast axonal transport of 3H-leucine-labelled protein were studied in vitro in the frog sciatic system. The methodology used made it possible to discriminate between effects on synthesis and transport of protein. The preparation which consisted of the dorsal ganglia, the sciatic nerve and the gastrocnemius muscle was placed in an incubation chamber. The ganglia were incubated in standard Ringer containing 3H-leucine and the nerve was prefused with modified Ringer. Perfusion of the nerve for 17 h with K+-free Ringer of Na+-free Ringer did not affect the rapid axonal transport of 3H-leucine-labelled material from the ganglia along the nerve towards a ligature in front of which it accumulated. Not was the transport influenced by concentrations of K+ up to 68.8 mM. In contrast concentrations exceeding 100 mM K+ partially inhibited the transport. Inhibition by ouabain (0.1 mM) was not prevented by elevating K+ to 30 mM, Deviation from isotonicity, towards a hypo- or a hypertonic medium, partially inhibited axonal transport. The transport inhibitory effects showed reversibility. Expermintal conditions, which arrested the transport, were tested in spearate experiments for effects on uptake of 3H-leucine into TCA-soluble and insoluble ganglionic components. K+ substituted for Na+, ouabain (0.1 mM) and hypotonic Ringer partially inhibited the amino acid uptake but also subsequent steps in the incorporation process, whereas only the latter was inhibited by hypertonic Ringer. The results are discussed in relation to possible changes in energy metabolism.

Animals↗
PubMed1996

Assembly of microfilaments and microtubules from axonally transported actin and tubulin after axotomy.

The slow component (SC) of axonal transport conveys structural proteins, regulatory proteins, and glycolytic enzymes toward the axon tip at 1-6 mm/day. Following axon interruption (axotomy), the rate of outgrowth corresponds to the rate of SCb-the fastest subcomponent of SC. Both axonal outgrowth and SCb accelerate 20-25% after axotomy. Tubulin and actin are the major proteins being carried by SCb. To further characterize the acceleration of SCb, we measured the equilibrium between subunits and polymers for both actin and tubulin. We radiolabeled newly synthesized proteins in rat motor neurons by microinjecting [35S]methionine into the spinal cord 7 days after crushing the sciatic nerve (85 mm from the spinal cord). Nerves were removed 7 days later for homogenization in polymer-stabilizing buffer (PSB) and centrifugation, followed by SDS-PAGE of supernatants (S) and pellets (P). We removed beta-tubulin, actin, and the medium-weight neurofilament protein (NF-M) from each gel by using the fluorogram as a template. After solubilizing gel segments for liquid scintillation spectrometry, we expressed counts as a polymerization ratio: P/[S+P]. In the nerve segments that contained radiolabeled Scb proteins, located 24-36 mm from the spinal cord, axotomy increased the polymerization ratio of SCb actin from 0.23 to 0.36 (P < 0.05) but had no effect on SCb beta-tubulin. In a separate experiment, we added 12 microM taxol to PSB to stabilize newly assembled microtubules. Adding taxol did not alter the polymerization ratio for SCb beta-tubulin in sham-axotomized nerves but aid increase the ratio in axotomized nerves, from 0.44 to 0.63 (P < 0.05); polymerization ratios for SCb actin were unaffected. We conclude that the assembly of microfilaments and microtubules increases to provide cytoskeletal elements for axon sprouts. The resulting loss of actin and tubulin subunits may play a role in the acceleration of SCb.

Actin Cytoskeleton↗
PubMed1981

Axonal transport of glycoproteins in regenerating olfactory nerve: enhanced glycopeptide concanavalin A-binding.

The size and concanavalin A-binding characteristics of glycopeptides derived from axonally transported glycoproteins were studied in regenerating garfish olfactory nerve. A regeneration related increase was observed in the proportion of total glycopeptide radioactivity associated with the lower molecular weight, dialyzable fraction. There was also a 3-5 fold increase in the axonal transport of low molecular weight concanavalin. A-binding glycopeptides in regenerating nerve. These results suggest a shift to an enhanced synthesis and axonal transport of glycoproteins containing low molecular weight, concanavalin A-binding carbohydrate chains in regenerating nerve.

Animals↗
PubMed1987

The use of the regenerating frog sciatic nerve for pharmacological studies of orthograde and retrograde axonal transport.

The outgrowth region of the regenerating frog sciatic nerve shows an increased permeability for various drugs, which has been utilized for pharmacological studies of axonal transport. Six days after a bilateral crush lesion, the nerves, including the spinal ganglia, were incubated in a compartmented chamber. Orthograde transport was assessed from the proximodistal distribution and the accumulation of labelled proteins in the nerve growth region. Retrograde transport was examined by allowing orthogradely transported materials to reverse at the regenerating region and then to accumulate at a ligature during a second incubation period. The distribution of radioactivity along the nerve was assayed by fluorography of whole-mount nerve preparations or by scintillation counting. Fluorography made it possible to increase the spatial resolution and to demonstrate effects in the elongating part of the regenerating nerve. Colchicine at low concentrations (10-100 microM) only inhibited axonal transport in the outgrowth region (6 mm long at 6 days after crush) and along some mm of the nerve proximal to the crush. Compound 48/80 (50 micrograms/ml), the most specific calmodulin inhibitor so far described, inhibited the transport along the same part of the nerve. Cytochalasin B (10 micrograms/ml) inhibited transport by effects limited to the outgrowth region. Both orthograde and retrograde transport showed sensitivity to these and some other drugs. The regenerating frog sciatic nerve seems to have significant advantages for pharmacological studies of axonal transport.

Animals↗