Editors' ChoicePhysiology

Summoning Schwann cells for neuromuscular recovery

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Science Signaling  17 Feb 2015:
Vol. 8, Issue 364, pp. ec35
DOI: 10.1126/scisignal.aaa9059

Motor neurons transmit impulses to muscle fibers through synapses called neuromuscular junctions (NMJs). Motor neuron degeneration is a characteristic of some peripheral neuropathies. Neurotoxins cause degeneration of the motor axon terminal, and recovery is assisted by local Schwann cells. Duregotti et al. found that injured motor neurons release danger signals that activate Schwann cells. Exposure to the black widow spider venom α-latrotoxin (α-LTX) or snake venom–derived taipoxin (TPX) induced the production of mitochondrial H2O2 in cultured primary rat motor neurons, as well as the release of mitochondrial DNA (mtDNA) and cytochrome c (Cyt c) into the culture medium. The phosphorylation of ERK (extracellular signal–regulated kinase) was increased in Schwann cells either cocultured with toxin-treated motor neurons or treated with H2O2, mtDNA, or Cyt c or a combination thereof. Phosphorylated ERK was also increased in NMJ-associated Schwann cells in mice injected subcutaneously with sublethal doses of the toxins. Pretreating these cocultures or mice with catalase, which converts H2O2 to water and O2, inhibited the increase in phosphorylated ERK. Pretreating mice with a MEK (ERK kinase) inhibitor delayed muscle recovery from α-LTX–induced paralysis. Isolated soleus muscles pretreated with catalase had decreased markers of synaptic regeneration after exposure to α-LTX. Exosomes secreted from toxin-treated motor neurons contained mtDNA, and phagocytic markers increased in NMJ-associated Schwann cells in isolated toxin-treated muscles. The findings suggest that injured motor neurons activate nearby Schwann cells to prevent the degeneration of neuromuscular junctions.

E. Duregotti, S. Negro, M. Scorzeto, I. Zornetta, B. C. Dickinson, C. J. Chang, C. Montecucco, M. Rigoni, Mitochondrial alarmins released by degenerating axon terminals activate perisynaptic Schwann cells. Proc. Natl. Acad. Sci. U.S.A. 112, E497–E505 (2015). [Abstract] [Full Text]

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