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.
Highlights
Organophosphate-induced delayed neuropathy (OPIDN) is a degenerative syndrome that results from exposure to organophosphates (OPs) found in pesticides and nerve agents
We cannot distinguish whether the lethality is solely due to neuropathologic effects or to effects of tri-ortho-cresyl phosphate (TOCP) on other tissues, these results show that TOCP treatment is deleterious to flies
TOCP treatment interferes with Protein Kinase A (PKA) activity We previously showed that Swiss Cheese (SWS), besides acting as a phospholipase, binds the C3 catalytic subunit of PKA, thereby inhibiting PKA activity [24]
Summary
Organophosphate-induced delayed neuropathy (OPIDN) is a degenerative syndrome that results from exposure to organophosphates (OPs) found in pesticides and nerve agents. OPIDN is characterized by a ‘‘dying-back’’ axonopathy leading to progressive limb weakness, abnormal reflexes, and paralysis which typically occur weeks or even months after exposure [1,2,3]. This syndrome was first described in 1930 after a poisoning epidemic in the southern United States, when thousands of people were paralyzed after consuming a beverage called Jamaica Ginger that contained the organophosphorus compound tri-ortho-cresyl phosphate (TOCP) [4]. It has been proposed that the aging reaction affects a non-esterase function of NTE, inducing a novel toxic function that is required for developing the full symptoms of OPIDN [11,12,16,17,18]
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