L’European Research Council accorde au Dr Nicolas Tricaud, chef d’équipe Avenir à l’INM, un financement d’excellence de près de 2 millions d’euros sur 5 ans pour étudier le rôle des mitochondries dans les maladies de la myéline.

ERC Starting Grants aim to support up-and-coming research leaders who are about to establish or consolidate an independent research team in Europe. The scheme targets promising researchers who have the proven potential of becoming independent research leaders. ERC Starting Grants amount up to 2.0 Mio Euro for a duration of up to 5 years.

Project Title and summary: Roles of mitochondria in healthy and diseased myelin-MitoMyelin.

Peripheral neuropathies form a diverse group of pathologies that include diabetic and aging peripheral neuropathies and inherited Charcot-Marie-Tooth diseases. These highly debilitating diseases that affect peripheral nerves structure and function represent an increasing burden in European societies. While the etiologies of these diseases are diverse, defects in mitochondrial morphology and functions have recently emerged as one major cause for these diseases. Some mitochondrial dysfunctions are known to affect neurons, but most of them appear to affect the myelinating Schwann cell that produces the myelin sheath. Intriguingly the specific disruption of mitochondria in these glial cells does not directly affect myelination but induces neurodegeneration, suggesting that the role of glial mitochondria is complex. 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 particular 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 and on axonal mitochondria using fluorescent probes expressed in myelinated axons. Reversely we will also modify axonal mitochondria and check the impact of these changes on myelin and glial mitochondria.

As the impact of mitochondrial dysfunctions in diseases and aging of the human nervous system is attracting more attention, deciphering the role of mitochondria in myelinating cells is essential. Indeed the concept of homeostatic interface between axon and glia 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.