Neurotoxic phospholipase A2 toxicity model

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 observed with the catalytically inactive, non-neurotoxic AtxA-homolog, ammodytin L (AtnL). Here we confirm 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.