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

Institute of Clinical Neuroimmunology, 81377 Munich, Germany
Biomedical Center (BMC), 82152 Planegg Martinsried, Germany
Institute of Neuronal Cell Biology, 80802 Munich, Germany
Max-Planck Institute of Neurobiology, 82152 Planegg-Martinsried, Germany
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany
German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany
Center of Integrated Protein Science (CIPSM), 81377 Munich, Germany

Research output: Contribution to journal › Article › Academic › peer-review

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
Publication status	Published - 20 Feb 2019
Externally published	Yes

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

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.",

author = "Witte, \{Maarten E.\} and Adrian-Minh Schumacher and Mahler, \{Christoph F.\} and Bewersdorf, \{Jan P.\} and Jonas Lehmitz and Alexander Scheiter and Paula S{\'a}nchez and Williams, \{Philip R.\} and Oliver Griesbeck and Ronald Naumann and Thomas Misgeld and Martin Kerschensteiner",

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Witte, ME, Schumacher, A-M, Mahler, CF, Bewersdorf, JP, Lehmitz, J, Scheiter, A, Sánchez, P, Williams, PR, 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, vol. 101, no. 4, pp. 615-624.e5. https://doi.org/10.1016/j.neuron.2018.12.023

TY - JOUR

T1 - Calcium Influx through Plasma-Membrane Nanoruptures Drives Axon Degeneration in a Model of Multiple Sclerosis

AU - Witte, Maarten E.

AU - Schumacher, Adrian-Minh

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

AU - Kerschensteiner, Martin

PY - 2019/2/20

Y1 - 2019/2/20

N2 - 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.

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.

UR - https://www.scopus.com/pages/publications/85060908288

UR - https://www.ncbi.nlm.nih.gov/pubmed/30686733

U2 - 10.1016/j.neuron.2018.12.023

DO - 10.1016/j.neuron.2018.12.023

M3 - Article

C2 - 30686733

SN - 0896-6273

VL - 101

SP - 615-624.e5

JO - Neuron

JF - Neuron

IS - 4

ER -

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

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