Project R-14281

Disturbances in Phospholipid Turnover in Charcot-Marie-Tooth disease Type 1A (Research)

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited disease of the peripheral nervous system, affecting 1 in 2500 individuals. CMT1A is caused by a PMP22-gene duplication and is characterised by peripheral nerve damage. CMT1A patients mainly experience severe muscle weakness, atrophy and sensory loss and often pain in the extremities, deteriorating over time and severely affecting the quality of life of CMT patients. To date, no treatment exists for CMT. The disease finds its cause in Schwann cells (SC) that can no longer efficiently wrap their membrane around nerves, making the nerves dysfunctional due to dysmyelination. The underlying mechanism is unknown. Yet, we do know that healthy SC membranes are heavily dependent on phospholipids, especially during myelination, a process that is severely altered in CMT1A. Therefore, I hypothesize that impaired phospholipid metabolism in Schwann cells causes myelination deficits in CMT1A. To test this hypothesis, I will use primary mouse SC and human iPSC-derived SC models. First, I will determine the disturbances in the phospholipidome. Next, I will examine the disturbances in phospholipid metabolism enzymes and transporters, and the effect of restoring the phospholipid metabolism on SC myelination. Finally, I will validate my findings and test the therapeutic interventions in a CMT1A mouse model. This study will provide new insights and molecular targets for the development of a treatment for CMT1A

01 November 2023 - 30 December 2027