Neurotoxic phospholipase A2 toxicity model : an insight from mammalian cells

Vardjan, Nina and Mattiazzi, Mojca and Rowan, Edward G. and Križaj, Igor and Petrovič, Uros̀ and Petan, Toni (2013) Neurotoxic phospholipase A2 toxicity model : an insight from mammalian cells. Communicative and Integrative Biology, 6 (3). e23600. ISSN 1942-0889

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    Abstract

    The molecular mechanism of action of presynaptically neurotoxic secreted phospholipases A2 (sPLA2s) has not been fully elucidated. We have recently proposed a model to explain one of the hallmarks of their action - the reduction in endocytosis leading to synaptic vesicle depletion in nerve terminals. Our results speak strongly in favor of a mechanism in which both specific protein-protein interactions and enzymatic activity of the neurotoxic sPLA2 ammodytoxin A (AtxA) are necessary for impairment of clathrin-dependent endocytosis in yeast cells. The reduction of endocytosis was strictly dependent on the enzymatic activity of sPLA2s expressed ectopically in our yeast model cells and was not observedwith the catalytically inactive, non-neurotoxic AtxA-homolog, ammodytin L (AtnL). Here weconfirm the validity of the model in mammalian cells also, by demonstrating that the enzymatically active mutant of AtnL, shown to inhibit endocytosis in yeast, acts as a presynaptically neurotoxic sPLA2 at the mammalian neuromuscular junction.