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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

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 3

Mitochondrial calcium release through VDAC1 induces SC demyelination.

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Mitochondrial calcium release through VDAC1 induces SC demyelination.
(A...
(A) Western blot analysis of phosphorylated ERK1/2, p38, JNK, c-JUN, BCL-2, cleaved caspase-3, total JNK, and c-JUN 4 hours or 12 hours after crush, with or without TRO19622 treatment or without crush but with MJ treatment. GAPDH was used as loading control. Blots are from samples run on parallel gels. n = 3–4 mice for each group. (B and C) Immunohistochemistry for nuclear phospho–c-JUN in mSCs of crushed or noncrushed control nerves after (B) VDAC1 silencing or (C) MJ or TRO19622 treatment. Mice were treated with TRO19622 intraperitoneally for 4 days before crush and via nerve injection 30 minutes before crush or treated with MJ via nerve injection 30 minutes before crush. Nerves were analyzed 12 hours after crush or injection. Representative images are shown. mSCs are stained for nuclei (TOPRO3, blue or white) and phospho–c-JUN (red), and infected cells express GFP (green). Arrows indicate infected mSC nuclei. Scale bar: 50 μm. Quantification of fluorescence intensity as fold over noncrushed nerve (basal). (D) Immunohistochemistry for total c-JUN in mSCs after VDAC1 silencing (shRNA) or blocking (TRO19622) and crush. Arrows indicate VDAC1 shRNA–infected mSC nuclei. Scale bar: 50 μm Quantification of total c-JUN represented as fold over basal (noncrushed mice). Noninfected neighbor cells were used as internal controls. (E) Representative images of myelinating and demyelinating SCs expressing GFP after crush or drug treatments. Scale bar: 100 μm. Quantification of myelinating and demyelinating SC frequency after (F) VDAC1 silencing and (G) MJ and TRO19622 treatment. Data are expressed as the mean ± SEM. n = 3–5 mice for each group. Asterisks and pound signs mark statistical differences compared with noncrushed and crushed nerves, respectively. *P < 0.05, #P < 0.05, **P < 0.01, ##P < 0.01, ***P < 0.001, ###P < 0.001, 2-tailed Student’s t test.

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