Liver X Receptor: a key player in myelination process and remyelination after injurie, by Charbel Massaad

Summary: Liver X Receptor: a key player in myelination process and remyelination after injuries

The peripheral nervous system is characterized by a unique symbiotic relationship between nerve fibers and their associated myelinating glial cells, the Schwann cells, which ensure axonal function and rapid nerve conduction. During peripheral nerve development, Schwann cells undergo a sequential developmental lineage transition from Schwann cell precursors to immature and finally myelinating Schwann cells, and any perturbation of Schwann cell lineage progression entails severe impairment of motor and sensory function. Importantly, many key regulators of SC development remain crucial for the generation and differentiation of the Schwann cell repair cell, which drives peripheral nerve regeneration.

We identified an essential novel role for the liver X receptor ß (LXRß), a member of the nuclear receptor family of transcription factors and regulator of lipid metabolism, in early SC development. We showed that this receptor is involved in myelination process in the central and peripheral nervous systems. Furthermore, it plays a crucial role in the regulation of redox homeostasis in the nerve. Its activation alleviates from oxidative stress elicited by diabetic injuries in the nerve, leading to a protection from diabetic neuropathies.

When we conditionally ablated LXRß specifically in SC precursors at embryonic day 12.5 (E12.5), peripheral nerves showed a developmental arrest at early embryonic stages and, postnatally, a dramatically reduced SC number along with a complete absence of myelinated axons. LXRß mutant mice developed a severe limb paralysis and died prematurely at the age of 7 months.

The presentation will provide novel insight into the fundamental, yet unexplored role of LXRβ in Schwann cell development and regeneration and will open new therapeutic perspectives based on LXR modulation. Indeed, as this nuclear receptor constitutes a hub of lipid metabolism, cholesterol homeostasis, redox status stabilization and Schwann cell development, we propose that LXR signaling can be considered as a major regulator in peripheral nerve glial cell function, and hence provides a promising targetable pathway for treating PNS myelin-related diseases.

Short biography:

Charbel Massaad is a Professor of Neuroscience and Molecular Biology since 2006. He received his PhD in 1998 and his HDR in 2004. He is the group leader of Myelination and Nervous system pathologies (https://t3s-1124.biomedicale.parisdescartes.fr/nos-equipes-de-recherche/equipe-102/)in the Inserm UMR 1124 (environmental Toxicity, Therapeutic Targets, cellular Signalling and Biomarkers). He is also the Dean of the Faculty of Basic and Biomedical Sciences at University of Paris since 2011. He is an Adjunct Professor at the American University of Beirut (Lebanion) and Hangzhou Dianzi University (China).

Pr. Massaad works on myelin physiology and pathophysiology since 2000. He focuses his work on identifying new signaling pathways implicated in myelination. Drugs targeting these pathways are then used for remyelination. He has a renowned expertise in oxidative stress. His team has developed several approaches to study myelination: molecular and cellular biology, confocal, electron and atomic force microscopies, infra-red spectroscopy, behavior…

His research is supported by grants from the ANR (French National Agency for Research), ARSEP (Association for MS), AFM (French association for myopathies), ERA-NET Neuron, Initiative of Excellence (idex), Inserm, CNRS. For these projects, he collaborates with national and international renowned research groups. He receives an award for Scientific Excellence (PES/PEDR), CNU section 64 since 2005. He is the author of 76 publications in peer-reviewed Journals and 5 patents.

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