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Mitochondrial alarmins released by degenerating motor axon terminals activate perisynaptic Schwann cells.

ABSTRACT: An acute and highly reproducible motor axon terminal degeneration followed by complete regeneration is induced by some animal presynaptic neurotoxins, representing an appropriate and controlled system to dissect the molecular mechanisms underlying degeneration and regeneration of peripheral nerve terminals. We have previously shown that nerve terminals exposed to spider or snake presynaptic neurotoxins degenerate as a result of calcium overload and mitochondrial failure. Here we show that toxin-treated primary neurons release signaling molecules derived from mitochondria: hydrogen peroxide, mitochondrial DNA, and cytochrome c. These molecules activate isolated primary Schwann cells, Schwann cells cocultured with neurons and at neuromuscular junction in vivo through the MAPK pathway. We propose that this inter- and intracellular signaling is involved in triggering the regeneration of peripheral nerve terminals affected by other forms of neurodegenerative diseases.

SUBMITTER: Duregotti E

PROVIDER: S-EPMC4321248 | biostudies-other | 2015 Feb

REPOSITORIES: biostudies-other

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Mitochondrial alarmins released by degenerating motor axon terminals activate perisynaptic Schwann cells.

Duregotti Elisa E Negro Samuele S Scorzeto Michele M Zornetta Irene I Dickinson Bryan C BC Chang Christopher J CJ Montecucco Cesare C Rigoni Michela M

Proceedings of the National Academy of Sciences of the United States of America 20150120 5

An acute and highly reproducible motor axon terminal degeneration followed by complete regeneration is induced by some animal presynaptic neurotoxins, representing an appropriate and controlled system to dissect the molecular mechanisms underlying degeneration and regeneration of peripheral nerve terminals. We have previously shown that nerve terminals exposed to spider or snake presynaptic neurotoxins degenerate as a result of calcium overload and mitochondrial failure. Here we show that toxin- ...[more]

PMID: 25605902

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Project description:A comparison between the axon terminals of octopaminergic efferent dorsal or ventral unpaired median neurons in either desert locusts (Schistocerca gregaria) or fruit flies (Drosophila melanogaster) across skeletal muscles reveals many similarities. In both species the octopaminergic axon forms beaded fibers where the boutons or varicosities form type II terminals in contrast to the neuromuscular junction (NMJ) or type I terminals. These type II terminals are immunopositive for both tyramine and octopamine and, in contrast to the type I terminals, which possess clear synaptic vesicles, only contain dense core vesicles. These dense core vesicles contain octopamine as shown by immunogold methods. With respect to the cytomatrix and active zone peptides the type II terminals exhibit active zone-like accumulations of the scaffold protein Bruchpilot (BRP) only sparsely in contrast to the many accumulations of BRP identifying active zones of NMJ type I terminals. In the fruit fly larva marked dynamic changes of octopaminergic fibers have been reported after short starvation which not only affects the formation of new branches ("synaptopods") but also affects the type I terminals or NMJs via octopamine-signaling (Koon et al., 2011). Our starvation experiments of Drosophila-larvae revealed a time-dependency of the formation of additional branches. Whereas after 2 h of starvation we find a decrease in "synaptopods", the increase is significant after 6 h of starvation. In addition, we provide evidence that the release of octopamine from dendritic and/or axonal type II terminals uses a similar synaptic machinery to glutamate release from type I terminals of excitatory motor neurons. Indeed, blocking this canonical synaptic release machinery via RNAi induced downregulation of BRP in neurons with type II terminals leads to flight performance deficits similar to those observed for octopamine mutants or flies lacking this class of neurons (Brembs et al., 2007).

Dataset Information

Mitochondrial alarmins released by degenerating motor axon terminals activate perisynaptic Schwann cells.

Publications

Mitochondrial alarmins released by degenerating motor axon terminals activate perisynaptic Schwann cells.

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