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Blocking mitochondrial calcium release in Schwann cells prevents demyelinating neuropathies
Sergio Gonzalez, … , Guy Lenaers, Nicolas Tricaud
Sergio Gonzalez, … , Guy Lenaers, Nicolas Tricaud
Published February 15, 2016
Citation Information: J Clin Invest. 2016;126(3):1023-1038. https://doi.org/10.1172/JCI84505.
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Research Article Cell biology Neuroscience Article has an altmetric score of 11

Blocking mitochondrial calcium release in Schwann cells prevents demyelinating neuropathies

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Abstract

Schwann cells produce myelin sheath around peripheral nerve axons. Myelination is critical for rapid propagation of action potentials, as illustrated by the large number of acquired and hereditary peripheral neuropathies, such as diabetic neuropathy or Charcot-Marie-Tooth diseases, that are commonly associated with a process of demyelination. However, the early molecular events that trigger the demyelination program in these diseases remain unknown. Here, we used virally delivered fluorescent probes and in vivo time-lapse imaging in a mouse model of demyelination to investigate the underlying mechanisms of the demyelination process. We demonstrated that mitochondrial calcium released by voltage-dependent anion channel 1 (VDAC1) after sciatic nerve injury triggers Schwann cell demyelination via ERK1/2, p38, JNK, and c-JUN activation. In diabetic mice, VDAC1 activity was altered, resulting in a mitochondrial calcium leak in Schwann cell cytoplasm, thereby priming the cell for demyelination. Moreover, reduction of mitochondrial calcium release, either by shRNA-mediated VDAC1 silencing or pharmacological inhibition, prevented demyelination, leading to nerve conduction and neuromuscular performance recovery in rodent models of diabetic neuropathy and Charcot-Marie-Tooth diseases. Therefore, this study identifies mitochondria as the early key factor in the molecular mechanism of peripheral demyelination and opens a potential opportunity for the treatment of demyelinating peripheral neuropathies.

Authors

Sergio Gonzalez, Jade Berthelot, Jennifer Jiner, Claire Perrin-Tricaud, Ruani Fernando, Roman Chrast, Guy Lenaers, Nicolas Tricaud

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Figure 7

Blocking VDAC1 activity prevents demyelination and improves neuromuscular performance in the CMT1A rat model.

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Blocking VDAC1 activity prevents demyelination and improves neuromuscula...
(A) Sciatic nerve Western blot analysis of WT and CMT1A rats in basal conditions, WT rats treated with MJ, and CMT1A rats treated with TRO19622 for 15 or 30 days or 2 months after ending treatment. GAPDH was used as loading control. n = 3 rats for each treatment. (B) Immunohistochemistry for phospho–c-JUN in mSCs of WT and CMT1A rats in basal conditions, WT rats treated with MJ, and CMT1A rats treated with vehicle or TRO19622 for 30 days. Scale bar: 50 μm. Quantification of phospho–c-JUN intensity. n = 3–6 rats for each treatment. (C) Representative transmission electron micrograph images of sciatic nerve cross sections of WT and CMT1A rats after vehicle or TRO19622 treatment. Scale bar: 5 μm. (D) Scatterplot showing the g-ratio plotted against the axon diameter of sciatic nerve fibers from WT and CMT1A rats after vehicle or TRO16922 treatment. n = 3 rats for each group. (E) Average myelin g-ratio, axonal diameter, and myelinated axon number in WT and CMT1A rats described in D. (F) Representative electrophysiological traces of sciatic nerve recording after stimulation of WT and CMT1A rats before and after TRO19622 treatment. Stimulus artifact (black arrowhead) and CMAP onset (white arrowhead) are shown. (G) Quantification of CMAP and NCV from F. (H) Accelerating rotarod latency, (I) grip strength, (J) time animals stand on each of their paws (time stand), (K) distance between paws, and (L) paw area of WT and CMT1A rats during vehicle or TRO19622 treatments. n = 6–10 rats for each group. Data are expressed as mean ± SEM. Asterisks and pound signs mark statistical differences compared with control and CMT1A rats treated with vehicle, respectively. *P < 0.05, #P < 0.05, **P < 0.01, ##P < 0.01, 1-way ANOVA followed by a Dunnett’s multiple comparison post-hoc test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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