Blocking mitochondrial calcium release in Schwann cells prevents demyelinating neuropathies.

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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 126 Issue 3 Pg. 1023-38 (Mar 01 2016) ISSN: 1558-8238 [Electronic] United States
• PMID: 26878172 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Calcium Channel Blockers
• Cholestenones
• Vdac1 protein, mouse
• olesoxime
• Voltage-Dependent Anion Channel 1
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Calcium Channel Blockers (pharmacology)
• Calcium Signaling
• Cell Line
• Charcot-Marie-Tooth Disease (drug therapy)
• Cholestenones (pharmacology)
• Demyelinating Diseases (drug therapy, metabolism, pathology)
• Diabetic Neuropathies (drug therapy, metabolism)
• Drug Evaluation, Preclinical
• Female
• Male
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, Obese
• Mice, SCID
• Mitochondria (metabolism)
• Myelin Sheath (drug effects, pathology)
• Peripheral Nerves (drug effects, pathology)
• Rats
• Schwann Cells (drug effects, physiology)
• Voltage-Dependent Anion Channel 1 (antagonists & inhibitors, metabolism)