Norepinephrine transporter defects lead to sympathetic hyperactivity in stem cell and mouse models of Familial Dysautonomia

Familial dysautonomia (FD) is a rare neurodevelopmental and neurodegenerative disorder that affects the sympathetic nervous system. Patients harbor a mutation in ELP1 yet, how loss of Elp1 affects the function of symNs remains unresolved. Such an understanding is critical since the most debilitating hallmarks of the disease include cardiovascular instability, dysautonomic crises and renal failure, which all result from dysregulated sympathetic activity. Here, we employ the human pluripotent stem cell (hPSC) technology as a modeling system to understand human, sympathetic neuron (symN)-specific disease mechanisms and provide a platform for drug testing and discovery. We show that FD symNs are intrinsically hyperactive in vitro, in co-cultures with cardiomyocyte target tissue and in FD animal models. We show that ELP1-rescued isogenic lines remain hyperactive, suggesting a different/additional disease mechanism. Accordingly, we report decreased intracellular norepinephrine (NE) levels, decreased NE re-uptake via NET and excessive extracellular NE in FD symNs. Finally, we performed a mini drug screen showing that current and new candidate drugs were able to lower hyperactivity. These findings may have implications for other peripheral nervous system disorders. Our drug screening platform may allow future drug testing and discovery for such disorders.