Dynamics Of REMYelination: study of nodes of Ranvier reassembly and its impact on repair – DOREMY

Myelination of axons is an essential step to ensure the rapid propagation of action potentials by saltatory conduction, a mechanism that relies on the nodes of Ranvier. These short unmyelinated axonal domains are highly enriched in voltage-gated sodium channels (Nav), which allow the regeneration and propagation of the action potentials by depolarization of the plasma membrane. Cell adhesion molecules, such as neurofascin-186 (Nfasc186) and contactin, as well as scaffold proteins (AnkyrinG and ßIVspectrin), are also enriched at the nodes and play a critical role in assembly and/or stabilization of Nav clusters.
Multiple Sclerosis (MS) is an automimmune demyelinating disease of the central nervous system (CNS), which corresponds to the first source of non traumatic neurological handicap in young adults in Europe and the USA. It is a complex disease with an inflammatory process associated to demyelinating attacks, followed by repair of the lesioned brain and spinal cord. The repair process (remyelination), relying on precursor cells of the oligodendrocytes (the myelinating glial cells of the CNS) can be extensive, but remains most of the time insufficient, leading to irreversible damages of the denuded axons associated with permanent neurological deficits. Treatments available presently only target the immune aspect of MS, and although they allow to decrease the frequency of relapses, their efficiency on long term progression of the disease is not proven. Promoting repair in order to protect axons and limit handicap progression is thus one of the key challenges in MS.
My present project is part of the studies of the mechanisms implicated in CNS remyelination, and aims at understanding the mechanism underlying nodes of Ranvier reassembly and its functional impact during repair.
The analysis of MS brain tissues, as well as MS experimental models, have indeed demonstrated the profound alterations of nodes of Ranvier in the demyelinated lesions and recent studies even suggested that nodal and perinodal components might be particularly vulnerable area of axonal damage. The analysis of partially remyelinated area showed that the repair process is associated with early nodal reclustering which can be detected prior to remyelination. Recently, we showed that this “prenodal” clustering is associated with increased axonal conduction velocity in vitro. This raises the hypothesis that nodal reclustering could influence axonal physiology and remyelination.
Although recent data have highlighted our understanding of the mechanisms of nodal formation in the peripheral nervous system (PNS), the nature of the signal(s) controlling the nodal clustering in the CNS remains largely unknown. Various works suggest the presence of complementary (or alternative) mechanisms of nodal assembly in the CNS compared to the PNS, but the exact chronology of assembly of the nodal proteins, and their respective role in its initiation are still to be described, in particular regarding neuronal subtypes variations. Furthermore, the mechanisms underlying nodal reclustering during remyelination and its impact are presently unknown.
To better characterize nodal (re)assembly during both development and remyelination, I developed various live-imaging set-ups ex vivo and in vivo, which will be completed by further innovative approaches (optogenetics, label-free imaging) to follow in real time the reassembly of the nodes of Ranvier during remyelination, their interaction with the surrounding glial cells, and evaluate its functional impact on remyelination and axonal physiology. The potential influence of nodal reassembly on myelinic and axonal repair will in particular be evaluated with the goal of identifying therapeutical targets to pave the way to new remyelinating strategies and promote neuroprotection in MS.
In the longer term, I wish to adapt these approaches to study nodes of Ranvier and myelin plasticity in other normal and pathological contexts.