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Dis Model Mech. 2017 May 1;10(5):597-603. doi: 10.1242/dmm.027870. Epub 2017 Jan 6.

Schwann cells are activated by ATP released from neurons in an in vitro cellular model of Miller Fisher syndrome.

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Department of Biomedical Sciences, University of Padua, Padua 35131 Italy.
Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands.
CNR Institute of Neuroscience, Padua 35131, Italy.
Department of Neurology, Mishima Hospital, Niigata 940-2302, Japan
Department of Biomedical Sciences, University of Padua, Padua 35131 Italy


The neuromuscular junction is exposed to different types of insult, including mechanical trauma, toxins and autoimmune antibodies and, accordingly, has retained through evolution a remarkable ability to regenerate. Regeneration is driven by multiple signals that are exchanged among the cellular components of the junction. These signals are largely unknown. Miller Fisher syndrome is a variant of Guillain-Barré syndrome caused by autoimmune antibodies specific for epitopes of peripheral axon terminals. Using an animal model of Miller Fisher syndrome, we recently reported that a monoclonal anti-polysialoganglioside GQ1b antibody plus complement damages nerve terminals with production of mitochondrial hydrogen peroxide, which activates Schwann cells. Several additional signaling molecules are likely to be involved in the activation of the regeneration program in these cells. Using an in vitro cellular model consisting of co-cultured primary neurons and Schwann cells, we found that ATP is released by neurons injured by the anti-GQ1b antibody plus complement. Neuron-derived ATP acts as an alarm messenger for Schwann cells, where it induces the activation of intracellular pathways, including calcium signaling, cAMP and CREB, which, in turn, produce signals that promote nerve regeneration. These results contribute to defining the cross-talk taking place at the neuromuscular junction when it is attacked by anti-gangliosides autoantibodies plus complement, which is crucial for nerve regeneration and is also likely to be important in other peripheral neuropathies.


ATP; Calcium; Miller Fisher syndrome; Phospho-CREB; Schwann cells; cAMP

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