I have been working for several years on a group of snake presynaptic neurotoxins from Elapid snakes endowed with PLA2 activity. Our laboratory has clarified their molecular mechanism of action: by cleaving phospholipids on the presynaptic plasma membrane they generate lysophospholipids and fatty acids, whose accumulation induces conformational changes in the lipid bilayer, thus favouring the exocytosis of the ready-to-release pool of vesicles and inhibiting vesicle retrieval, eventually leading to unbalanced exo-excytosis. Moreover, by altering plasma membrane permeability to calcium, they induce a toxic calcium influx within nerve terminals. In turn, this triggers nerve degeneration and paralysis of the neuromuscular junction (NMJ).

Strikingly, the neuroparalysis induced by these and other animal neurotoxins is fully reversible: indeed within few days the NMJ recovers functionally both in mice and humans, making these toxins a powerful tool to study within a short time window the molecular mechanisms underlying peripheral nerve regeneration following an acute degeneration.

By combining transcriptomics, electrophysiology and imaging approaches, we are currently investigating the cross-talk taking place at the murine NMJ between damaged nerve terminals, peripheral Schwann cell and the muscle, with the aim of identifying molecules and pathways promoting nerve terminal recovery of function.

Editor’s Choice: Leslie K. Ferrarelli. Summoning Schwann cells for neuromuscular recovery. Science Signalling (2015) 8, Issue 364, p. ec35 DOI: 10.1126/scisignal.aaa9059 a commento del paper Duregotti et al., 2015 PNAS 112 (5), pp. E497-E505.

Best poster prize at the World IST meeting in Glasgow (2006): “CALCIUM INFLUX AND MITOCHONDRIAL ALTERATIONS AT SYNAPSES EXPOSED TO SNAKE NEUROTOXINS OR THEIR PHOSPHOLIPID HYDROLYSIS PRODUCTS”.

Perspective by Zimmerberg and Chernomordik published in Science (2005), 310:1626-1627 as comment of the paper by Rigoni et al., (2005) Science 310, 1678-1680.

• Negro, S., Lessi, F., Duregotti, E., Aretini, P., La Ferla, M., Franceschi, S., Menicagli, M., Bergamin, E., Radice, E., Thelen, M., Megighian, A., Pirazzini, M., Mazzanti, C.M., Rigoni, M., Montecucco, C. (2017) CXCL12α/SDF-1 from perisynaptic Schwann cells promotes regeneration of injured motor axon terminals. EMBO Molecular Medicine, 9 (8), 1000-1010
• Duregotti E, Negro S, Scorzeto M, Zornetta I, Dickinson BC, Chang CJ, Montecucco C, Rigoni M. (2015) Mitochondrial alarmins released by degenerating motor axon terminals activate perisynaptic Schwann cells. Proc Natl Acad Sci U S A. 112(5), E497-505
• Rigoni, M., Pizzo, P., Schiavo, G., Weston, A.E., Zatti, G., Caccin, P., Rossetto, O., Pozzan, T. and Montecucco, C. (2007) Calcium influx and mitochondrial alterations at synapses exposed to snake neurotoxins or their phospholipid hydrolysis products. J Biol Chem 282, 11238-11245
• Rigoni, M., Caccin, P., Gschmeissner, S., Rossetto, O., Schiavo, G. and Montecucco, C. (2005) Equivalent effects of snake PLA2 neurotoxins and lysophospholipid-fatty acid mixtures. Science 310, 1678-1680
• Rigoni, M., Schiavo, G., Weston, A., Caccin, P., Allegrini, F., Valtorta, F., Pennuto, M., Montecucco, C. and Rossetto, O. (2004) Snake presynaptic neurotoxins with phospholipase A2 activity induce punctate swellings of neurites and exocytosis of synaptic vesicles. J Cell Sci 117, 3561-3570

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