MITOMYELIN · Roles of mitochondria in healthy and diseased myelin

Demyelinating peripheral neuropathies form a diverse group of pathologies that include diabetic and aging peripheral neuropathies and inherited Charcot-Marie-Tooth diseases. Mitochondrial dysfunctions have recently emerged as one major cause for these diseases. The goal of this project is to investigate the role of mitochondria in healthy and diseased myelin and to test whether we can change mitochondrial status and functions to prevent or treat these diseases. Our working hypothesis is that glial mitochondria act as a homeostatic interface between axon and glia: they participate to the destabilization of Schwann cells during demyelination and they help to detoxify axons by scavenging reactive oxygen species produced by axonal mitochondria. We have developed a novel approach that uses viral vectors to express cDNAs and/or small inhibitory RNAs in myelinating Schwann cells and myelinated axons in mice in vivo. I propose to use this approach combined with state-of-the-art imaging technique to challenge this preliminary concept in a meaningful in vivo context. Viral tools will first be used to generate defects in mitochondrial functions in the myelinating Schwann cell. The impact on myelination and myelin maintenance will be assessed by light and electron microscopy. Second, viruses will be used to express genetically-encoded fluorescent probes designed to analyze mitochondrial status in living cells. This imaging approach will allow investigating mitochondrial status in healthy, demyelinating and diseased myelinating Schwann cells in vivo. Finally we will investigate the impact of glial mitochondria dysfunctions on the axon. Reversely we will also modify axonal mitochondria and check the impact of these changes on myelin and glial mitochondria. This concept will be highly relevant to understand the molecular mechanisms of peripheral neuropathies but also of brain diseases such as multiple sclerosis, Alzheimer’s, Parkinson’s and Huntington’s diseases.