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Methylmercury causes neuronal cell death through the suppression of the TrkA pathway: In vitro and in vivo effects of TrkA pathway activators. Fujimura, Masatake, E-mail: fujimura nimd. Methylmercury MeHg is an environmental toxin which induces cell death specific for the nervous systems.

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Here we show that MeHg causes neuronal cell death through the suppression of the tropomyosin receptor kinase A TrkA pathway, and that compounds activating the TrkA pathway prevent MeHg-induced nerve damage in vitro and in vivo. We first investigated the mechanism of MeHg-induced neurotoxicity in differentiating neurons using PC12 cells.

To determine the mechanism of MeHg-induced apoptosis, we evaluated the effects of MeHg on the TrkA pathway, which is known to regulate neuronal differentiation and viability. Western blot analysis demonstrated that, like the TrkA phosphorylation inhibitor Ka, MeHg inhibited phosphorylation of TrkA and its downstream effectors.

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Finally, we demonstrated that MCC rescued the clinical and pathological changes in MeHg-exposed rats. Overexpression of functional TrkA receptors after internalisation in human airway smooth muscle cells. Trafficking of the TrkA receptor after stimulation by NGF is of emerging importance in structural cells in the context of airway inflammatory diseases.

We have here studied the TrkA trafficking mechanisms in these cells. Co-immunoprecipitation of clathrin-TrkA was revealed, and TrkA internalisation inhibited either by clathrin inhibitors or by siRNA inducing downregulation of endogenous clathrin. TrkA internalised receptors were totally degraded in lysosomes, with no recycling phenomenon.

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Newly synthesized TrkA receptors were thereafter re-expressed at the cell membrane within 10 h. TrkA re-synthesis was inhibited by blockade of clathrin-dependent internalisation, but not of TrkA receptors lysosomal degradation. In conclusion, we show here the occurrence of clathrin-dependent TrkA internalisation and lysosomal degradation in the airway smooth muscle, followed by upregulated re-synthesis of functional TrkA receptors and increased proliferative effect in the human airway smooth muscle.

This may have pathophysiological consequences in airway inflammatory diseases. Hereditary sensory and autonomic neuropathy type IV HSAN IV is an autosomal recessive disorder characterized by a complete lack of pain perception and anhidrosis. GE, p. LP, p. IT, p. CS, p. CS, and p. RC, all of which were predicted pathogenic by in silico analysis.

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The allowed us to assess the pathogenicity of each mutation and to gain novel insights into tropomyosin receptor kinase A TRKA downstream aling. By corollary, the assessment of the clinical pathogenicity of HSAN IV mutations is more complex than initially predicted and requires a multifaceted approach.

Although TrkA postendocytic sorting ificantly influences neuronal cell survival and differentiation, the molecular mechanism underlying TrkA receptor sorting in the recycling or degradation pathways remains poorly understood.

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This work identifies GGA3 as a key player in a novel DXXLL-mediated endosomal sorting machinery that targets TrkA to the plasma membrane, where it prolongs the activation of Akt aling and survival responses. Directory of Open Access Journals Sweden. Full Text Available Sympathetic neurons require NGF from their target fields for survival, axonal target innervation, dendritic growth and formation, and maintenance of synaptic inputs from preganglionic neurons.

Target-derived NGF als are propagated retrogradely, from distal axons to somata of sympathetic neurons via TrkA aling endosomes. We report that a subset of TrkA endosomes that are transported from distal axons to cell bodies translocate into dendrites, where they are aling competent and move bidirectionally, in close proximity to synaptic protein clusters. Using a strategy for spatially confined inhibition of TrkA kinase activity, we found that distal-axon-derived TrkA aling endosomes are necessary within sympathetic neuron dendrites for maintenance of synapses.

Thus, TrkA aling endosomes have unique functions in different cellular compartments. Moreover, target-derived NGF mediates circuit formation and synapse maintenance through TrkA endosome aling within dendrites to promote aggregation of postsynaptic protein complexes. Neurotrophin receptors are emerging targets in oncology, but their clinicopathologic ificance in thyroid cancer is unclear.

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Nerves in the tumor microenvironment were positive for TrkA. Together, these data reveal TrkAp75 NTRand sortilin as potential therapeutic targets in thyroid cancer. Published by Elsevier Inc. All rights reserved. Furthermore, how it contributes to leukemogenesis is unknown. Here, we describe a molecular network that is important for TrkA function in leukemogenesis. Moreover, endogenous TrkA associated with c-Src complexes was detected in leukemia.

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These data suggest that TrkA plays a key role in leukemogenesis and reveal an unexpected physiological role for TrkA in the pathogenesis of leukemia. These data have important implications for understanding various hematological malignancies. aling of nerve growth factor NGF and its receptor TrkA promotes neuronal differentiation, synapse formation and survival.

It has been known that the complex of NGF and TrkA is internalized into the cytoplasm and transported for further al transduction, but the ultrastructural information of this process is virtually unknown. In order to clarify the relationship between the internalization of TrkA and the membrane-associated proteins caveolin and clathrinthe localization and three-dimensional structures of those proteins were examined with computer tomography of high voltage electron microscopy in PC12 cells.

TrkA immunoreactivity was found only at definite areas in the plasma membrane, as ring and cluster structures. Its 3D image indicated that those cluster structures contained small pits, which did not appear to be typical caveolae in size and shape. Caveolin-1 immunoreactivity was found as a mesh-like structure just beneath the plasma membrane.

These suggest that clathrin rather than caveolin is mainly involved in the process of TrkA internalization, at least in differentiated PC12 cells.

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Two classes of astrocytes in the adult human and pig retina in terms of their expression of high affinity NGF receptor TrkA. Astrocytes have been implicated in axon guidance and synaptic regeneration in the retina and these processes involve activation of the high affinity nerve growth factor receptor, known as the tyrosine kinase A TrkA receptor. The purpose of the present study was to characterize the expression of TrkA in astrocytes of the adult pig and human retina.

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To this end, sections of human and pig retinas were immunolabeled with a combination of antibodies to glial fibrillary acidic protein GFAP and TrkA. Our study revealed that most of the GFAP-positive cells express TrkAwhereas a rare, novel subpopulation of astrocytes was found to be devoid of TrkA. Our support the idea that astrocytes play an important neurotrophic role in the retina. Three-cohort targeted gene screening reveals a non-synonymous TRKA polymorphism associated with schizophrenia.

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A meta-analysis revealed ten non-synonymous SNPs that were nominally associated with schizophrenia, nine of which have not been ly linked Thus, TRKA aling may represent a novel susceptibility pathway Here we report that Trks are frequently overexpressed in hepatocellular carcinoma HCC from patients and human liver cancer cell lines.

To unravel the underlying molecular mechanism s for this phenomenon, DNA methylation patterns of CpG islands in TrkATrkB, and TrkC genes were examined in normal and cancer cell lines derived from liver. A good correlation was observed between promoter hypermethylation and lower expression of TrkATrkB, and TrkC genes, which was supported by the data that inhibiting DNA methylation with 5-azacytidine restored expression of those genes in normal liver cell lines.

Furthermore, Trks promoted the proliferation of HepG2 and induced expression of the metastatic regulator, Twist. These suggest that Trks may contribute to growth and metastasis of liver cancer. In our work, we used an in vitro culture model to investigate whether antidepressant imipramine Ip may protect bupivacaine Bv -induced neurotoxicity in mouse dorsal root ganglion DRG. Ip protected Bv-induced apoptosis and neurite loss in DRG.

The naked mole-rat is a subterranean rodent lacking several pain behaviors found in humans, rats, and mice. For example, nerve growth factor NGFan important mediator of pain sensitization, fails to produce thermal hyperalgesia in naked mole-rats. Between one- and three-amino-acid substitutions in the kinase domain of the naked mole-rat TrkA are sufficient to render the receptor hypofunctional, and this is associated with the absence of heat hyperalgesia.

Our data suggest that evolution has selected for a TrkA variant that abolishes a robust nociceptive behavior in this species but is still compatible with species fitness. Full Text Available The naked mole-rat is a subterranean rodent lacking several pain behaviors found in humans, rats, and mice. For example, nerve growth factor NGF, an important mediator of pain sensitization, fails to produce thermal hyperalgesia in naked mole-rats.

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BFCNs extend their axons to the hippocampus where they bind nerve growth factor NGF which is retrogradely transported to the cell body. Twenty-four hours after a single injection of pro-NGF into hippocampus, we found increased hippocampal p75NTR levels, decreased hippocampal TrkA levels, and cholinergic degeneration. The data suggest that the increase in p75NTR with AD may be mediated by elevated pro-NGF levels as a result of decreased cleavage, and that pro-NGF may be partially responsible for age-related degenerative changes observed in the basal forebrain.

Full Text Available Abstract In order to investigate the expression levels of nerve growth factor NGF and its receptors TrkA and p75 in prehierarchical follicles and oviducts of hens, five day-old laying hens were examined by immunohistochemistry and RT-PCR analysis. NGF and its receptors were expressed in theca cells and granulosa cells of prehierarchical follicles, and they were also expressed in the epithelial cells of oviducts. The expression of the genes NGF, TrkA and p75 were ificantly different in prehierarchical follicles p TrkA gene expression was ificantly different in different parts of oviduct p TrkA in small yellow follicle SYF.

In the oviduct, the expression of NGF was the highest in infundibulum, and lowest in isthmus.

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These suggest that NGF may play an important role in the regulation of hen reproduction. Effects of short-term hormonal replacement on learning and on basal forebrain ChAT and TrkA content in ovariectomized rats. It has been proposed that sex steroid hormones improve performance in some cognitive tasks by regulating the basal forebrain cholinergic function.

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