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PubMedDate not supplied

A paradigm for examining toxicant effects on viability, structure, and axonal transport of neurons in culture.

N1E.115 murine neuroblastoma cells differentiating in serum-free medium were used to develop a paradigm for testing neurotoxicity in vitro. The paradigm was designed to test the effects of toxicants on four different aspects of cell function or structure: 1. Viability as shown by the retention of cellular radiolabel (51Cr); 2. Growth and maintenance of neurites as reflected by the incidence and average length of these processes; 3. Gross structure of neurites; and 4. Velocity and flux of rapid anterograde and retrograde axonal transport as judged by video-enhanced differential interference contrast microscopy. To evaluate this paradigm, colchicine and vinblastine were used as neurotoxicants with a well-understood mechanism of action. These agents were only weakly cytotoxic according to the Cr-release assay, but were able to interfere with neurite outgrowth at nanomolar concentrations. Neurites that were elaborated in the presence of vinblastine and colchicine were often disfigured by numerous swellings packed with organelles. In established neurites, micromolar concentrations of vinblastine inhibited organellar motility with great rapidity, blocking all signs of transport within 20 min. The effect of colchicine was slower and less complete, but still impressive. We suggest that this four-part analysis represents a highly sensitive in vitro test for neurotoxicity, and a means of analyzing the relation between abnormalities of transport and structural damage of nerve cells.

Animals↗
PubMed2005

The axonal transport of mitochondria.

Organelle transport is vital for the development and maintenance of axons, in which the distances between sites of organelle biogenesis, function, and recycling or degradation can be vast. Movement of mitochondria in axons can serve as a general model for how all organelles move: mitochondria are easy to identify, they move along both microtubule and actin tracks, they pause and change direction, and their transport is modulated in response to physiological signals. However, they can be distinguished from other axonal organelles by the complexity of their movement and their unique functions in aerobic metabolism, calcium homeostasis and cell death. Mitochondria are thus of special interest in relating defects in axonal transport to neuropathies and degenerative diseases of the nervous system. Studies of mitochondrial transport in axons are beginning to illuminate fundamental aspects of the distribution mechanism. They use motors of one or more kinesin families, along with cytoplasmic dynein, to translocate along microtubules, and bidirectional movement may be coordinated through interaction between dynein and kinesin-1. Translocation along actin filaments is probably driven by myosin V, but the protein(s) that mediate docking with actin filaments remain unknown. Signaling through the PI 3-kinase pathway has been implicated in regulation of mitochondrial movement and docking in the axon, and additional mitochondrial linker and regulatory proteins, such as Milton and Miro, have recently been described.

Animals↗
PubMed1981

Somatopetal axonal transport of fluorescent lectins: distribution pattern and cytophotometric quantification in mouse peripheral neurons.

Six FITC-labeled lectins (Con A, WGA, SBA, DBA, UeA 1, PNA) with different carbohydrate specificities were injected into the snout region of 12-day-old mice. WGA, and to a lesser extent Con A, accumulated in trigeminal and facial neurons as a result of somatopetal axonal transport. Only an occasional trigeminal neuron was labeled after injection of SBA and DBA. None of the other lectins were incorporated. WGA and Con A were used for cytophotometric quantification of neuronal accumulation of transported FITC-lectins in isolated neurons from trigeminal ganglia. This technique makes it possible to study changes in neuronal lectin binding sites and adsorptive endocytosis during different physiological and pathological states.

Animals↗
PubMed1990

Retrograde axonal transport of mercury in primary sensory neurons innervating the tooth pulp in the rat.

The pulp cavity of the first upper molar was exposed unilaterally in adult rats with a dental drill and about 1 microliter of mercuric chloride was injected into the coronal pulp. The rats were killed after 1-24 days and frozen sections from the trigeminal ganglia were subjected to silver acetate autometallography for demonstration of mercury. Mercury was found to have accumulated in neurons of the ipsilateral trigeminal ganglion by retrograde axonal transport. The possible implications of this finding are discussed.

Afferent Pathways↗
PubMed1982

Specificity of axonal transport in C2, a histaminergic neuron of Aplysia californica.

Several labeled neurotransmitter substances or precursors ( [3H]histamine, [3H]serotonin, and [3H]choline) were injected with pressure into the cell body of C2, an identified putative histaminergic neuron in the cerebral ganglion of Aplysia in order to study the selectivity of axonal transport. We examined transport of these substances along the posterior lip nerve which contains one of the 3 extraganglionic axons of C2. The distribution of radioactivity along this axon indicated that some of the [3H]histamine is moved by fast transport, and some by diffusion. The velocity at which [3H]histamine moved along the axon was estimated at approximately 50 mm per day at 23 degrees C. The movement was slower at lower temperatures, and was partially inhibited by colchicine. Transport was selective: 6 h after injection of [3H]histamine into the cell body of C2, most of the radioactivity that appeared in axons was in the form of histamine. In contrast, equal amounts of the labeled amine and its metabolite, gamma-glutamylhistamine, were found in the cell body. Fast transport was not observed when [3H]serotonin or [3H]choline were injected. Subcellular fractionation experiments after injection showed that [3H]histamine was enriched in particulate fractions; [3H]gamma-glutamylhistamine was recovered only in the soluble fraction. Packaging of [3H]histamine in C2 was not affected by treatment with reserpine; in contrast, subcellular fractionation experiments indicated that reserpine blocks the uptake of [3H]histamine into vesicles in the giant cerebral neuron, an identified serotonergic Aplysia cell.

Animals↗
PubMed1996

Filament heterogeneity within the dystrophic neurites of senile plaques suggests blockage of fast axonal transport in Alzheimer's disease.

In this study, the direct comparison of biopsy and autopsy tissue by morphological and immunocytochemical techniques, respectively, was used to document cytoskeletal changes of dystrophic neurites (DN) of senile plaques in Alzheimer's disease. This dual approach demonstrated several unreported abnormalities which, together with analogous findings in several experimental models, suggest that DN are associated with deficiencies in fast axonal transport and replacement of the cytoskeleton by an array of related abnormal filaments.

Actin Cytoskeleton↗
PubMed2002

Charcot-Marie-Tooth disease neurofilament mutations disrupt neurofilament assembly and axonal transport.

Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system, and mutations in neurofilaments have been linked to some forms of CMT. Neurofilaments are the major intermediate filaments of neurones, but the mechanisms by which the CMT mutations induce disease are not known. Here, we demonstrate that CMT mutant neurofilaments disrupt both neurofilament assembly and axonal transport of neurofilaments in cultured mammalian cells and neurones. We also show that CMT mutant neurofilaments perturb the localization of mitochondria in neurones. Accumulations of neurofilaments are a pathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, and diabetic neuropathy. Our results demonstrate that aberrant neurofilament assembly and transport can induce neurological disease, and further implicate defective neurofilament metabolism in the pathogenesis of human neurodegenerative diseases.

Animals↗
PubMed1987

Distribution and orthograde axonal transport of HRP in feline eyes following intravitreal injection: an ultrastructural study.

The retina and optic nerve in the cat were examined by electron microscopy at five different time periods (1-, 3-, 8-, 16- and 24 hr) following the injection of horseradish peroxidase (HRP) into the vitreous cavity. Intra- and intercellular HRP was found in ganglion cells, Müller cells and horizontal cells even at 1 hr. Intra-axonal HRP in the retina and the retrolaminar optic nerve was seen most frequently at 3- and 8 hr. At 16- and 24 hr, many phagocytes containing HRP were noted in the nerve-fibre layer; subsequently HRP activity decreased throughout the retina. On the other hand, HRP activity in the intracanalicular optic nerve was significantly increased at 16 hr. Intra-axonal HRP appeared to be morphologically distributed in two forms: (i) HRP granules bound by a single-unit membrane mostly 0.1-0.4 micron in diameter; (ii) granules less than 0.05 micron which were occasionally hard to distinguish from artefacts such as stain deposit. The rate of orthograde axonal transport of HRP granules larger than 0.05 micron was examined on the basis of the frequency of HRP granules appearing in the retrolaminar and intracanalicular parts of the optic nerves. Though the rate seemed to be widely variable, the major velocity was calculated to be 45 mm per day, which is equal to intermediate axonal flow rates.

Animals↗
PubMedDate not supplied

Relative susceptibility of cytoskeleton-associated and soluble neurofilament subunits to aluminum exposure in intact cells. A possible mechanism for reduction of neurofilament axonal transport during aluminum neurotoxicity.

Previous studies have demonstrated the appearance of phosphorylated neurofilament (NF) subunits within perikaryal cytoskeletons following aluminum exposure. In order to examine the mechanisms leading to this altered distribution of NF subunits, we carried out biochemical analyses of NF subunits in Triton-insoluble and -soluble fractions derived from aluminum-treated NB2a/d1 cells. In addition to increases in the Triton-insoluble cytoskeleton, increases in all three NF subunits were also detected within the Triton-soluble fraction of aluminum-treated cells. To address the nature of this increase in Triton-soluble subunits, aluminum-treated and untreated cultures were harvested in the absence of Triton and fractionated by established procedures to yield fractions greatly enriched for perikarya and neurites, respectively. Each of these subcellular fractions was then subjected to further homogenization in the presence of 1% Triton and centrifugation to yield Triton-insoluble cytoskeletons and Triton-soluble material derived from perikarya and axonal neurites, respectively. Resulting Triton-soluble fractions were "clarified" by high-speed centrifugation to eliminate oligomeric assemblies or soluble neurofilaments. Immunoblot analysis demonstrated quantitative recovery of the aluminum-induced increase in Triton-soluble NF subunits in the perikaryal fraction. Additional aluminum-treated and untreated cultures were pulse-chase radiolabeled with [35S]methionine and fractionated into Triton-insoluble and soluble fractions from isolated perikarya and axonal neurites. Autoradiographic analysis of immunoprecipitated NF subunits revealed that aluminum treatment delayed the translocation of newly synthesized subunits into neurites and resulted in the accumulation of radiolabeled subunits within the Triton-soluble fraction of perikarya. These findings suggest that aluminum may exert a relatively greater effect on NF subunits that have not yet undergone axonal transport and/or incorporation into Triton-insoluble structures vs those that have already deposited into axons. This possibility was supported by the observation that a higher concentration of aluminum was required to alter the electrophoretic migration of in vitro reassembled neurofilaments vs that required for unassembled NF subunits. These findings provide possible mechanisms for the accumulation of NF subunits in perikarya during aluminum intoxication.

Aluminum↗