Morphometric characterization of the neuromuscular junction of rodents intoxicated with 2,4-dithiobiuret: evidence that nerve terminal recycling processes contribute to muscle weakness

Rheuben, Mary B.; Autio, Dawn M.; Xu, You Fen; Atchison, William D.

doi:10.1016/j.taap.2004.01.004

Cited by 7 publications

(2 citation statements)

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“…The capacity of the STOP null axons to regenerate and project toward the OB glomeruli favors the second hypothesis. The tubulovesicular structures were similar to those observed in nerve terminals of the neuromuscular junction following intoxication with 2,4-dithiobiuret that are associated with a decrease of synaptic vesicles density, suggesting an impairment of vesicle release and recycling [27]. At the presynaptic level, STOP protein is phosphorylated by calmodulin-dependant protein kinase II, an enzyme involved in synaptic plasticity.…”

Section: Discussionsupporting

confidence: 57%

Loss of STOP Protein Impairs Peripheral Olfactory Neurogenesis

et al. 2010

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BackgroundSTOP (Stable Tubulin-Only Polypeptide) null mice show behavioral deficits, impaired synaptic plasticity, decrease in synaptic vesicular pools and disturbances in dopaminergic transmission, and are considered a neurodevelopmental model of schizophrenia. Olfactory neurons highly express STOP protein and are continually generated throughout life. Experimentally-induced loss of olfactory neurons leads to epithelial regeneration within two months, providing a useful model to evaluate the role played by STOP protein in adult olfactory neurogenesis.Methodology/Principal FindingsImmunocytochemistry and electron microscopy were used to study the structure of the glomerulus in the main olfactory bulb and neurogenesis in the neurosensorial epithelia. In STOP null mice, olfactory neurons showed presynaptic swellings with tubulovesicular profiles and autophagic-like structures. In olfactory and vomeronasal epithelia, there was an increase in neurons turnover, as shown by the increase in number of proliferating, apoptotic and immature cells with no changes in the number of mature neurons. Similar alterations in peripheral olfactory neurogenesis have been previously described in schizophrenia patients. In STOP null mice, regeneration of the olfactory epithelium did not modify these anomalies; moreover, regeneration resulted in abnormal organisation of olfactory terminals within the olfactory glomeruli in STOP null mice.Conclusions/SignificanceIn conclusion, STOP protein seems to be involved in the establishment of synapses in the olfactory glomerulus. Our results indicate that the olfactory system of STOP null mice is a well-suited experimental model (1) for the study of the mechanism of action of STOP protein in synaptic function/plasticity and (2) for pathophysiological studies of the mechanisms of altered neuronal connections in schizophrenia.

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Section: Discussionsupporting

confidence: 57%

Loss of STOP Protein Impairs Peripheral Olfactory Neurogenesis

et al. 2010

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“…There is growing evidence that the function of chemical synapses in the peripheral nervous system (PNS) and central nervous system (CNS) can be disrupted by many structurally dissimilar electrophilic neurotoxicants, e.g., acrylamide, 2,4dithiobiuret, methylmercury, acrolein, and diethyldithiocarbamate (Table 1; Atchison and Narahasi, 1982;Atchinson et al, 1982;Danscher et al, 1973;Lowndes, 1979, 1981;LoPachin et al, 2004;Xu et al, 2002). Results from corresponding research have suggested both pre-and postsynaptic sites (e.g., neurotransmitter postsynaptic receptors and presynaptic uptake, storage, and release) as possible targets for these chemicals (LoPachin et al, 2004(LoPachin et al, , 2006aLovell et al, 2000;Nagendra et al, 1997;Rheuben et al, 2004;Vaccari et al, 1998). Whereas the molecular mechanisms of these synaptic toxicants are poorly understood, they share the ability to form adducts with or otherwise modify nucleophilic sulfhydryl groups (Barber and LoPachin, 2004;Clarkson, 1972;Kruzer, 1956;Witz, 1989).…”

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confidence: 99%

Synaptic Cysteine Sulfhydryl Groups as Targets of Electrophilic Neurotoxicants

LoPachin

Barber

2006

Toxicological Sciences

114

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Many structurally diverse chemicals (e.g., acrylamide, 2,4-dithiobiuret, methylmercury) are electrophiles and cause synaptic dysfunction by unknown mechanisms. The purpose of this Forum review is to discuss the possibility that highly nucleophilic cysteine thiolate groups within catalytic triads of synaptic proteins represent specific and necessary targets for electrophilic neurotoxicants. Most of these toxicants share the ability to adduct or otherwise modify nucleophilic sulfhydryl groups. It is also now recognized that synaptic activity is regulated by the redox state of certain cysteine sulfhydryl groups on proteins. Electrophilic neurotoxicants might, therefore, produce synaptic toxicity by modifying these thiols. Because most proteins contain cysteine residues, target specificity is an issue that significantly detracts from the mechanistic validity of this hypothesis. However, recent research indicates that these thiolates are receptors for the endogenous nitric oxide (NO) pathway and that subsequent reversible S-nitrosylation finely regulates a broad spectrum of synaptic activities. We hypothesize that electrophilic neurotoxicants selectively adduct/derivatize NO-receptor thiolates in catalytic triads and that the resulting loss of fine gain control impairs neurotransmission and produces neurotoxicity. This proposal has mechanistic implications for a large class of electrophilic chemicals used in the agricultural and industrial sectors. In addition, research based on this hypothesis could provide mechanistic insight into neurodegenerative conditions such as Parkinsonism and Alzheimer's disease that presumably involve endogenous production of neurotoxic electrophiles (e.g., acrolein, 4-hydroxy-2-nonenal). The proposed mechanism of electrophilic neurotoxicants represents a new and exciting experimental framework for mechanistic research in human neuropathological conditions associated with toxicant exposure or disease-based processes.

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Tautomeric preferences and electron delocalization in biurets, thiobiurets, and dithiobiurets: Anab initiostudy

Adane¹,

Bharatam²

2008

Int J of Quantum Chemistry

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ABSTRACT:In several literature reports biuret and its sulfur analogs are reported to exist in their diketo form with general formula H 2 NOCXONHOCYONH 2 (X ϭ O, Y ϭ O, biuret; X ϭ Y ϭ S, dithiobiuret; and X ϭ O, Y ϭ S, thiobiuret). On the other hand, recently reported results on the electronic structure of biguanide analogs (X ϭ Y ϭ NH) demonstrated that a form equivalent to diketo is not the preferred structure. Thus, a systematic ab initio study on the tautomeric preferences of biuret and its sulfur analogs (dithiobiuret and thiobiuret) has been carried out. The results indicate that an interplay of conjugative stabilization and intramolecular hydrogen bonding to play a role in tautomeric preferences. Energy and geometric parameters, natural bond orbital analyses have been employed to understand the chemistry of the title compounds. The results indicate that unlike biguanides, these compounds prefer diketo forms containing hydrogen on the bridging nitrogen (N4) and in a trans-arrangement (1a-4a). However, tautomerization of these keto forms to the corresponding enol isomers was also found to be highly probable.

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Morphometric characterization of the neuromuscular junction of rodents intoxicated with 2,4-dithiobiuret: evidence that nerve terminal recycling processes contribute to muscle weakness

Cited by 7 publications

References 50 publications

Loss of STOP Protein Impairs Peripheral Olfactory Neurogenesis

Loss of STOP Protein Impairs Peripheral Olfactory Neurogenesis

Synaptic Cysteine Sulfhydryl Groups as Targets of Electrophilic Neurotoxicants

Tautomeric preferences and electron delocalization in biurets, thiobiurets, and dithiobiurets: Anab initiostudy

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