Project R-13216

Charcot-Marie-Tooth Disease Type 1A: Traffic jam at the Kennedy Tunnel. (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. During adolescence, CMT1A patients mainly experience severe weakness, atrophy and sensory loss in the lower legs and hands, among other symptoms. Despite being known about for over a century, no drug treatment options exist today. The disruption of the peripheral nerves is known to be caused by Schwann cells (SC) that can no longer wrap their membrane around nerves and thus make the nerves dysfunctional. Although we do not know how this happens, we do know that healthy SC membranes are heavily dependent on phospholipids and cholesterol, which seem to be strongly altered in CMT1A. Therefore, I hypothesize that impaired phospholipid and cholesterol homeostasis in Schwann cells causes myelination deficits in CMT1A. To test this hypothesis, we will use both mouse SCs and human skin cell-derived SCs. First, I will reveal if the phospholipid and cholesterol metabolism is disturbed. Next, I will examine the effect of phospholipid and cholesterol metabolism interventions on SC myelination. Finally, I will validate my findings and test the interventions from the human cell experiments in our CMT1A mouse model. This study will provide new insights and molecular targets for the development of a first CMT1A drug treatment.

01 November 2022 - 31 October 2026