Calcium overload in nerve terminals of cultured neurons intoxicated by alpha-latrotoxin and snake PLA2 neurotoxins

Tedesco, Erik; Rigoni, Michela; Caccin, Paola; Grishin, Eugene V.; Rossetto, Ornella; Montecucco, Cesare

doi:10.1016/j.toxicon.2009.03.025

Cited by 54 publications

(35 citation statements)

References 41 publications

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“…Bulges are sites of calcium overload and accumulation of depolarized mitochondria (18), and the MitoPY1 signal indicates that these mitochondria produce H 2 O 2 . Quantification of the signals indicates a more pronounced effect of α-Ltx with respect to Tpx, in agreement with the fact that the pore formed by the former neurotoxin mediates a larger Ca 2+ entry than Tpx (21). Similar results were obtained following intoxication of rat spinal cord motor neurons (MNs; Fig.…”

Section: Resultssupporting

confidence: 81%

“…Similar to α-Ltx, SPANs-induced peripheral paralysis is followed by a complete recovery: regeneration and functional reinnervation are almost fully restored in rats by 5 d (20). The similar outcome and time-course of the paralysis induced by the two types of presynaptic neurotoxins suggest that the common property of inducing Ca 2+ entry into the nerve terminals is the main cause of nerve terminal degeneration (21). Indeed, these neurotoxins cause activation of the calcium-activated calpains that contribute to cytoskeleton fragmentation (22).…”

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confidence: 78%

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

Duregotti

Negro

Scorzeto

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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105

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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.motor axon degeneration | presynaptic neurotoxins | mitochondrial alarmins | Schwann cells

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Section: Resultssupporting

confidence: 81%

mentioning

confidence: 78%

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

Duregotti

Negro

Scorzeto

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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105

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“…Neuronal bulging also occurs in primary neurons exposed to spider and snake neurotoxins, which cause a degeneration of nerve terminals mainly due to a toxic Ca 2+ overload. Such bulges are at least in part the result of an unbalanced exo-endocytosis, and are sites of vesicular markers accumulation (Tedesco et al, 2009). MAC was found to accumulate within bulges (Fig.…”

Section: Resultsmentioning

confidence: 99%

An animal model of Miller Fisher syndrome: Mitochondrial hydrogen peroxide is produced by the autoimmune attack of nerve terminals and activates Schwann cells

Rodella

Scorzeto

Duregotti

et al. 2016

Neurobiology of Disease

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The neuromuscular junction is a tripartite synapse composed of the presynaptic nerve terminal, the muscle and perisynaptic Schwann cells. Its functionality is essential for the execution of body movements and is compromised in a number of disorders, including Miller Fisher syndrome, a variant of Guillain-Barré syndrome: this autoimmune peripheral neuropathy is triggered by autoantibodies specific for the polysialogangliosides GQ1b and GT1a present in motor axon terminals, including those innervating ocular muscles, and in sensory neurons. Their binding to the presynaptic membrane activates the complement cascade, leading to a nerve degeneration that resembles that caused by some animal presynaptic neurotoxins. Here we have studied the intra- and inter-cellular signaling triggered by the binding and complement activation of a mouse monoclonal anti-GQ1b/GT1a antibody to primary cultures of spinal cord motor neurons and cerebellar granular neurons. We found that a membrane attack complex is rapidly assembled following antibody binding, leading to calcium accumulation, which affects mitochondrial functionality. Consequently, using fluorescent probes specific for mitochondrial hydrogen peroxide, we found that this reactive oxygen species is rapidly produced by mitochondria of damaged neurons, and that it triggers the activation of the MAP kinase pathway in Schwann cells. These results throw light on the molecular and cellular pathogenesis of Miller Fisher syndrome, and may well be relevant to other pathologies of the motor axon terminals, including some subtypes of the Guillain Barré syndrome.

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“…Phospholipase A2 activity is thought to be associated with Ca 21 handling. It has been shown that snake PLA2 neurotoxins induced Ca 21 overload in nerve terminals of cultured neurons [Tedesco et al, 2009]. Lupescu et al [2006] reported that human parvovirus B19 capsid protein VP1-evoked Ca 21 influx was inhibited if phospholipase A2 activity was suppressed.…”

Section: Discussionmentioning

confidence: 99%

Maprotiline‐induced Ca²⁺ fluxes and apoptosis in human osteosarcoma cells

Liao

Huang

et al. 2010

Drug Development Research

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The effect of maprotiline on cytosolic free Ca2+ concentrations ([Ca2+]i) and cell viability was explored in human osteosarcoma cells (MG63), using the fluorescent dyes fura‐2 and WST‐1, respectively. Maprotiline at concentrations of ≥20 µM increased [Ca2+]i in a concentration‐dependent manner. The Ca2+ signal was reduced partly by removing extracellular Ca2+. The maprotiline‐induced Ca2+ influx was sensitive to inhibition by aristolochic acid (a phospholipase A2 inhibitor). In Ca2+‐free medium, after treatment with 1 µM thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor), 200 µM maprotiline failed to induce a [Ca2+]i rise. At concentrations of 50–100 µM maprotiline killed cells in a concentration‐dependent manner. The cytotoxic effect of 60 µM maprotiline was slightly enhanced by prechelating cytosolic Ca2+ with 1,2‐bis(2‐aminophenoxy)ethane‐N,N,N′,N′‐tetraacetic acid (BAPTA). Propidium iodide staining data suggested that maprotiline induced apoptosis between concentrations of 60–70 µM, which was enhanced by BAPTA. Collectively, in MG63 cells, maprotiline induced [Ca2+]i rises by causing Ca2+ release from the endoplasmic reticulum and Ca2+ influx from phospholipase A2‐regulated Ca2+ channels. Furthermore, maprotiline caused apoptosis that was regulated by Ca2+. Drug Dev Res 71: 268–274, 2010. © 2010 Wiley‐Liss, Inc.

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Calcium overload in nerve terminals of cultured neurons intoxicated by alpha-latrotoxin and snake PLA2 neurotoxins

Cited by 54 publications

References 41 publications

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

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

An animal model of Miller Fisher syndrome: Mitochondrial hydrogen peroxide is produced by the autoimmune attack of nerve terminals and activates Schwann cells

Maprotiline‐induced Ca²⁺ fluxes and apoptosis in human osteosarcoma cells

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Calcium overload in nerve terminals of cultured neurons intoxicated by alpha-latrotoxin and snake PLA2 neurotoxins

Cited by 54 publications

References 41 publications

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

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

An animal model of Miller Fisher syndrome: Mitochondrial hydrogen peroxide is produced by the autoimmune attack of nerve terminals and activates Schwann cells

Maprotiline‐induced Ca2+ fluxes and apoptosis in human osteosarcoma cells

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Maprotiline‐induced Ca²⁺ fluxes and apoptosis in human osteosarcoma cells