SIGMA-CMT2A

Charcot-Marie-Tooth disease type 2A (CMT2A) is a rare inherited sensory motor neuropathy that affects peripheral nerve axons. To date, no treatment to halt the progression of the pathology is available. This disorder is due to mutations in Mitofusin 2 (MFN2), protein that is mainly localized in the outer mitochondrial membrane where it regulates mitochondrial fusion. A fraction of MFN2 is also localized to membranes of the endoplasmic reticulum (ER), allowing the formation of a highly organized domain called mitochondria-associated ER membranes (MAMs). Those MAMs are essential for the proper functioning of the mitochondria, the powerhouse of the cell. Interestingly, Sigma-1 receptor (S1R), an ER-localized transmembrane chaperone, may be targeted by small molecules to restore mitochondrial and MAM alteration. Therefore, our aim is to demonstrate the therapeutic value of S1R activation to treat CMT2A. For that purpose, we are developing novel highly selective S1R agonists in a drug discovery program. We will compare the efficacy of up to three optimized leads with the reference S1R agonist, PRE-084, on the locomotor deficits and mitochondrial dysfunction observed in CMT2A Drosophila models. Then, the most efficient novel S1R agonist will be further validated with PRE-084 in a CMT2A murine model, by analyzing behavioral (locomotion, coordination) and electrophysiological (hearing, vision) outcomes. We will unravel the neuroprotective mechanisms of S1R activation by using motor and sensory neurons differentiated from human induced pluripotent stem cells. Analyses will focus on mitochondrial activity and dynamics, and on cell calcium handling, ER and oxidative stress, neuronal activity and neurite length. Moreover, to unravel novel signaling pathways modulated by the S1R activation, we will perform an unbiased analysis of the transcriptome and proteome on those cells. Ultimately, we are optimistic to propose a pharmacological treatment based on S1R to counteract CMT2A.