Glial diversity in chronic peripheral nerve disorders

• Applicant: Professor Dr. Robert Fledrich
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 404077973

Demyelinating polyneuropathies are characterized by a primary defect of Schwann cells which leads to a slowly progressive demyelination and a secondary axonal loss that underlies clinical impairment. Unfortunately, no causal therapy is available for the vast majority of demyelinating neuropathies, as the pathological mechanisms remain poorly understood.In previous studies we observed that individual Schwann cells display very different morphological and molecular characteristics in mouse models for demyelinating polyneuropathies. Indeed, in demyelinating polyneuropathies, myelin disassembly is not a concerted process of all Schwann cells, but occurs rather focally in individual cells. This fascinating observation has been described more than 60 years ago and is referred to as segmental demyelination that explains the slowly progressive nature of the disease. Why do individual Schwann cells disintegrate whereas others aligned with the very same nerve fiber remain intact?To answer this question I chose to combine new molecular and imaging techniques to (1) isolate and characterize specific Schwann cell populations that are prone to degeneration in mouse models for demyelinating polyneuropathies. The goal is to unravel the initial mechanisms of disease manifestation that are responsible for the subsequent process of demyelination. Vice versa, I am aiming at a better understanding of the repair mechanisms in peripheral nerves, given the fact that Schwann cells are in principle able to remyelinate demyelinated segments. However, Schwann cells lose their ability to reconstitute the original myelin sheath length during remyelination and consequently nerve function is only partially restored. By applying surgical and genetic techniques, I will (2) investigate the mechanisms of longitudinal myelin growth and the reassembly of myelin sheath segments in chronic nerve disorders. Here, both, longitudinal and radial myelin growth require an enormous metabolic effort, especially with regard to lipids, which constitute about 70% of the myelin sheath. Next to the Schwann cell intrinsic biosynthesis of lipids, circulating lipids appear to play an important role for Schwann cell function and systemic dyslipidemia has been suggested to play a central role in the pathomechanism of diabetic polyneuropathy. How do Schwann cells integrate lipid-associated Signals? To address this question I plan to (3) characterize mouse models for peripheral neuropathies with altered systemic lipid homeostasis. In addition, I will genetically manipulate regulatory pathways in Schwann cells that are linked to lipid metabolism.With the intended approaches it is not only my goal to gain insight into the profound disease- and repair mechanisms of demyelinating neuropathies, but also to substantially contribute to the development of new therapeutic strategies for this life-burdening diseases.

• DFG Programme: Independent Junior Research Groups