Calcium Influx through Plasma-Membrane Nanoruptures Drives Axon Degeneration in a Model of Multiple Sclerosis

Maarten E. Witte; Adrian Minh Schumacher; Christoph F. Mahler; Jan P. Bewersdorf; Jonas Lehmitz; Alexander Scheiter; Paula Sánchez; Philip R. Williams; Oliver Griesbeck; Ronald Naumann; Thomas Misgeld; Martin Kerschensteiner

doi:10.1016/j.neuron.2018.12.023

Calcium Influx through Plasma-Membrane Nanoruptures Drives Axon Degeneration in a Model of Multiple Sclerosis

Maarten E. Witte, Adrian Minh Schumacher, Christoph F. Mahler, Jan P. Bewersdorf, Jonas Lehmitz, Alexander Scheiter, Paula Sánchez, Philip R. Williams, Oliver Griesbeck, Ronald Naumann, Thomas Misgeld, Martin Kerschensteiner

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Abstract

Axon loss determines persistent disability in multiple sclerosis patients. Here, we use in vivo calcium imaging in a multiple sclerosis model to show that cytoplasmic calcium levels determine the choice between axon loss and survival. We rule out the endoplasmic reticulum, glutamate excitotoxicity, and the reversal of the sodium-calcium exchanger as sources of intra-axonal calcium accumulation and instead identify nanoscale ruptures of the axonal plasma membrane as the critical path of calcium entry. Witte et al. identify cytoplasmic calcium accumulations as a key driver of axon degeneration in a model of multiple sclerosis. Calcium accumulates in the axoplasm because nanoscale ruptures of the axonal plasma membrane provide an entry path for extracellular calcium.

Original language	English
Pages (from-to)	615-624.e5
Journal	Neuron
Volume	101
Issue number	4
DOIs	https://doi.org/10.1016/j.neuron.2018.12.023
State	Published - Feb 20 2019

Keywords

axon degeneration
calcium imaging
experimental autoimmune encephalomyelitis
in vivo microscopy
multiple sclerosis
plasma membrane

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10.1016/j.neuron.2018.12.023

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Witte, M. E., Schumacher, A. M., Mahler, C. F., Bewersdorf, J. P., Lehmitz, J., Scheiter, A., Sánchez, P., Williams, P. R., Griesbeck, O., Naumann, R., Misgeld, T., & Kerschensteiner, M. (2019). Calcium Influx through Plasma-Membrane Nanoruptures Drives Axon Degeneration in a Model of Multiple Sclerosis. Neuron, 101(4), 615-624.e5. https://doi.org/10.1016/j.neuron.2018.12.023

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abstract = "Axon loss determines persistent disability in multiple sclerosis patients. Here, we use in vivo calcium imaging in a multiple sclerosis model to show that cytoplasmic calcium levels determine the choice between axon loss and survival. We rule out the endoplasmic reticulum, glutamate excitotoxicity, and the reversal of the sodium-calcium exchanger as sources of intra-axonal calcium accumulation and instead identify nanoscale ruptures of the axonal plasma membrane as the critical path of calcium entry. Witte et al. identify cytoplasmic calcium accumulations as a key driver of axon degeneration in a model of multiple sclerosis. Calcium accumulates in the axoplasm because nanoscale ruptures of the axonal plasma membrane provide an entry path for extracellular calcium.",

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AU - Witte, Maarten E.

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AU - Mahler, Christoph F.

AU - Bewersdorf, Jan P.

AU - Lehmitz, Jonas

AU - Scheiter, Alexander

AU - Sánchez, Paula

AU - Williams, Philip R.

AU - Griesbeck, Oliver

AU - Naumann, Ronald

AU - Misgeld, Thomas

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AB - Axon loss determines persistent disability in multiple sclerosis patients. Here, we use in vivo calcium imaging in a multiple sclerosis model to show that cytoplasmic calcium levels determine the choice between axon loss and survival. We rule out the endoplasmic reticulum, glutamate excitotoxicity, and the reversal of the sodium-calcium exchanger as sources of intra-axonal calcium accumulation and instead identify nanoscale ruptures of the axonal plasma membrane as the critical path of calcium entry. Witte et al. identify cytoplasmic calcium accumulations as a key driver of axon degeneration in a model of multiple sclerosis. Calcium accumulates in the axoplasm because nanoscale ruptures of the axonal plasma membrane provide an entry path for extracellular calcium.

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KW - calcium imaging

KW - experimental autoimmune encephalomyelitis

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Calcium Influx through Plasma-Membrane Nanoruptures Drives Axon Degeneration in a Model of Multiple Sclerosis

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