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Neuron. 2019 Feb 20;101(4):615-624.e5. doi: 10.1016/j.neuron.2018.12.023. Epub 2019 Jan 24.

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

Author information

1
Institute of Clinical Neuroimmunology, University Hospital, Ludwig-Maximilians Universität München, Marchioninistraße 15, 81377 Munich, Germany; Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians Universität München, Großhaderner Strasse 9, 82152 Planegg Martinsried, Germany.
2
Institute of Clinical Neuroimmunology, University Hospital, Ludwig-Maximilians Universität München, Marchioninistraße 15, 81377 Munich, Germany; Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians Universität München, Großhaderner Strasse 9, 82152 Planegg Martinsried, Germany; Institute of Neuronal Cell Biology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany.
3
Institute of Neuronal Cell Biology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany.
4
Max-Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Planegg-Martinsried, Germany.
5
Max-Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
6
Institute of Neuronal Cell Biology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Feodor-Lynen-Straße 17, 81377 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Straße 17, 81377 Munich, Germany; Center of Integrated Protein Science (CIPSM), Butenandtstraße 5-13, 81377 Munich, Germany. Electronic address: thomas.misgeld@tum.de.
7
Institute of Clinical Neuroimmunology, University Hospital, Ludwig-Maximilians Universität München, Marchioninistraße 15, 81377 Munich, Germany; Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians Universität München, Großhaderner Strasse 9, 82152 Planegg Martinsried, Germany; Munich Cluster for Systems Neurology (SyNergy), Feodor-Lynen-Straße 17, 81377 Munich, Germany. Electronic address: martin.kerschensteiner@med.uni-muenchen.de.

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.

KEYWORDS:

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

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