Neurotoxic phospholipase A2 toxicity model: an insight from mammalian cells

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.