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Organophosphate-induced changes in the PKA regulatory function of Swiss Cheese/NTE lead to behavioral deficits and neurodegeneration.

ABSTRACT: Organophosphate-induced delayed neuropathy (OPIDN) is a Wallerian-type axonopathy that occurs weeks after exposure to certain organophosphates (OPs). OPs have been shown to bind to Neuropathy Target Esterase (NTE), thereby inhibiting its enzymatic activity. However, only OPs that also induce the so-called aging reaction cause OPIDN. This reaction results in the release and possible transfer of a side group from the bound OP to NTE and it has been suggested that this induces an unknown toxic function of NTE. To further investigate the mechanisms of aging OPs, we used Drosophila, which expresses a functionally conserved orthologue of NTE named Swiss Cheese (SWS). Treating flies with the organophosporous compound tri-ortho-cresyl phosphate (TOCP) resulted in behavioral deficits and neurodegeneration two weeks after exposure, symptoms similar to the delayed effects observed in other models. In addition, we found that primary neurons showed signs of axonal degeneration within an hour after treatment. Surprisingly, increasing the levels of SWS, and thereby its enzymatic activity after exposure, did not ameliorate these phenotypes. In contrast, reducing SWS levels protected from TOCP-induced degeneration and behavioral deficits but did not affect the axonopathy observed in cell culture. Besides its enzymatic activity as a phospholipase, SWS also acts as regulatory PKA subunit, binding and inhibiting the C3 catalytic subunit. Measuring PKA activity in TOCP treated flies revealed a significant decrease that was also confirmed in treated rat hippocampal neurons. Flies expressing additional PKA-C3 were protected from the behavioral and degenerative phenotypes caused by TOCP exposure whereas primary neurons were not. In addition, knocking-down PKA-C3 caused similar behavioral and degenerative phenotypes as TOCP treatment. We therefore propose a model in which OP-modified SWS cannot release PKA-C3 and that the resulting loss of PKA-C3 activity plays a crucial role in developing the delayed symptoms of OPIDN but not in the acute toxicity.

SUBMITTER: Wentzell JS

PROVIDER: S-EPMC3928115 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Organophosphate-induced changes in the PKA regulatory function of Swiss Cheese/NTE lead to behavioral deficits and neurodegeneration.

Wentzell Jill S JS Cassar Marlène M Kretzschmar Doris D

PloS one 20140218 2

Organophosphate-induced delayed neuropathy (OPIDN) is a Wallerian-type axonopathy that occurs weeks after exposure to certain organophosphates (OPs). OPs have been shown to bind to Neuropathy Target Esterase (NTE), thereby inhibiting its enzymatic activity. However, only OPs that also induce the so-called aging reaction cause OPIDN. This reaction results in the release and possible transfer of a side group from the bound OP to NTE and it has been suggested that this induces an unknown toxic func ...[more]

PMID: 24558370

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Project description:Reducing salt intake can mitigate the prevalence of metabolic disorders. In fermented foods such as cheeses, however, salt can impact the activity of desirable and undesirable microorganisms and thus affect their properties. This study aimed to investigate the effect of salt level on Swiss-type cheese ripening. Since proteolysis is a major event in cheese ripening, three strains of Lactobacillus helveticus were selected on the cell-envelope proteinase (CEP) they harbor. Their proteolytic activity on caseins was studied at six salt levels (0-4.5%) at pH 7.5 and 5.2. Swiss-type cheeses were manufactured at regular, increased, and decreased salt concentrations, and characterized for their composition and techno-functional properties. L. helveticus strains possessed and expressed the expected CEPs, as shown by PCR and shaving experiments. The two strains of L. helveticus that possessed at least the CEP PrtH3 showed the greatest proteolytic activity. Casein hydrolysis in vitro was similar or higher at pH 5.2, i.e., cheese pH, compared to pH 7.5, and slightly decreased at the highest salt concentrations (3.0 and 4.4%). Similarly, in ripened cheeses, these L. helveticus strains showed 1.5-2.4 more proteolysis, compared to the cheeses manufactured without L. helveticus. Regarding the salt effect, the 30% salt-reduced cheeses showed the same proteolysis as regular cheeses, while the upper-salted cheeses showed a slight decrease (-14%) of the non-protein fraction. The microbial and biochemical composition remained unchanged in the 30%-reduced cheeses. In contrast, Propionibacterium freudenreichii, used as ripening bacteria in Swiss cheese, grew more slowly in upper-salted (1.14%, w/w) cheeses, which induced concomitant changes in the metabolites they consumed (-40% lactic acid) or produced (fivefold decrease in propionic acid). Some cheese techno-functional properties were slightly decreased by salt reduction, as extrusion (-17%) and oiling off (-4%) compared to regular cheeses. Overall, this study showed that a 30% salt reduction has little impact in the properties of Swiss-type cheeses, and that starters and ripening cultures strains could be chosen to compensate changes induced by salt modifications in Swiss-type and other hard cheeses.

Dataset Information

Organophosphate-induced changes in the PKA regulatory function of Swiss Cheese/NTE lead to behavioral deficits and neurodegeneration.

Publications

Organophosphate-induced changes in the PKA regulatory function of Swiss Cheese/NTE lead to behavioral deficits and neurodegeneration.

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