Exploring the functions of selected histone demethylases in myelinating cells

• Applicant: Professorin Dr. Claire Jacob
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Developmental Neurobiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 538088008

The peripheral and central nervous systems (PNS and CNS, respectively) are constituted of neurons that carry the information in the form of electric signals, and of glial cells that have multiple roles in supporting neuronal functions. In this project, we are particularly interested in the functions of myelinating glial cells that build a thick myelin sheath rich in lipids around the axonal part of neurons to insulate axons, protect them from the external environment and allow fast conduction of electric signals along axons. Two types of myelinating cells exist, Schwann cells in the PNS and oligodendrocytes in the CNS. In case of a lesion, Schwann cells have the ability to change their identity to lose their myelin and convert into a repair cell that stimulates axonal regeneration and guide the regrowth of axons to their former target. Once axons have regrown, Schwann cells rebuild a myelin sheath around regenerated axons. In the CNS, myelinating oligodendrocytes do not have the ability to convert into repair cells and cannot stimulate axonal regrowth. In addition, their myelin contains proteins that send negative signals for axonal regrowth, thereby preventing regeneration. However, there are some cases where CNS lesions are only demyelinating: they lead to oligodendrocyte death, but leave axons intact. This type of lesion occurs in the course of a CNS degenerative disease called multiple sclerosis. In this case, remyelination can occur, but the efficiency of this process is limited, being efficient at the start of the disease and becoming inefficient as the disease progresses and with the age of the patient. Multiple sclerosis is the most frequent degenerative disease of the CNS and there is currently no available cure. In the PNS, axonal regeneration and remyelination after lesion are also age-dependent, becoming less efficient in old individuals. It is thus of utmost importance to identify treatments to improve axonal regeneration and remyelination. Our work shows that a type of proteins called chromatin-remodeling enzymes, which can control the activation of our genes, could be used to increase the efficiency of regeneration after lesion. This project will analyze the involvement of selected chromatin-remodeling enzymes called histone demethylases, in the development of Schwann cells and oligodendrocytes and in the regeneration process of the PNS and CNS after a traumatic lesion in the PNS and after a demyelinating lesion in the CNS.

• DFG Programme: Research Grants