Schwann cell demyelination is triggered by a transient mitochondrial calcium release through Voltage Dependent Anion Channel 1

Abstract

The maintenance of the myelin sheath by Schwann cells around peripheral nerve axons is essential for the rapid propagation of action potentials. A large number of peripheral neuropathies results for the loss of this myelin sheath, a process called demyelination. Demyelination is a program of cell dedifferentiation characterized by reprograming and several catabolic and anabolic events. This process was best characterized in Wallerian demyelination that occurs following nerve injury. In this model, the earliest well characterized steps are MAPK pathways activation and cJun phosphorylation and nuclear localization starting around 4hrs after nerve injury. Here we show, using in vivo imaging of virally-delivered fluorescent probes to mitochondria, that Schwann cell mitochondria pH, motility and calcium are altered as soon as 1hr after nerve injury. Mitochondrial calcium release through VDAC1 mitochondrial channel and mPTP directly induced Schwann cell demyelination via MAPK and c-Jun activation. Decreasing mitochondrial calcium release through VDAC1 silencing or TRO19622 blocking prevented MAPK and cJun activation and demyelination. VDAC1 opening with Methyl Jasmonate induced these cellular mechanisms in absence of nerve injury. Taken together, these data indicate that mitochondria calcium homeostasis through VDAC1 is instrumental in the Schwann cell demyelination process and therefore provide a molecular basis for an anti-demyelinating drug approach.

Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs

“…114,117,118,[123][124][125] Dysregulated myelination is a characteristic feature of numerous heritable neurological diseases, such as the PNS hereditary disorder, Charcot-Marie-Tooth disease, 126,127 X-linked adrenoleukodystrophy and metachromatic leukodystrophy, 128 hereditary diffuse leukoencephalopathy with spheroids, Nasu-Hakola disease, 114 and Huntington's disease, 129,130 among others. 55,131,132 A dysfunctional myelination apparatus is also evident in acquired demyelinating diseases such as diabetic peripheral neuropathy, drug-related peripheral neuropathies, leprosy, and peripheral neuropathies of inflammatory etiology. 132 Most interestingly, converging evidence drawn from ''Big Data'' analytics in parallel with epigenetic, neuroimaging, and experimental model investigations seems to connect an adult-onset form of attention-deficit/ hyperactivity disorder pathogenesis and persistence with dysregulated myelination.…”

“…55,131,132 A dysfunctional myelination apparatus is also evident in acquired demyelinating diseases such as diabetic peripheral neuropathy, drug-related peripheral neuropathies, leprosy, and peripheral neuropathies of inflammatory etiology. 132 Most interestingly, converging evidence drawn from ''Big Data'' analytics in parallel with epigenetic, neuroimaging, and experimental model investigations seems to connect an adult-onset form of attention-deficit/ hyperactivity disorder pathogenesis and persistence with dysregulated myelination. 133,134 Many risk genes for CNS disorders such as AD, PD, schizophrenia, autism, and MS have been unveiled by genome-wide association studies to be expressed by microglia.…”