Norepinephrine transporter defects lead to sympathetic hyperactivity in Familial Dysautonomia models
Date
2022-11
Journal Title
Journal ISSN
Volume Title
Publisher
Springer Science and Business Media LLC
Abstract
Familial dysautonomia (FD), a rare neurodevelopmental and neurodegenerative disorder affects the sympathetic and sensory nervous system. Although almost all patients harbor a mutation in ELP1, it remains unresolved exactly how function of sympathetic neurons (symNs) is affected; knowledge critical for understanding debilitating disease hallmarks, including cardiovascular instability or dysautonomic crises, that result from dysregulated sympathetic activity. Here, we employ the human pluripotent stem cell (hPSC) system to understand symN disease mechanisms and test candidate drugs. FD symNs are intrinsically hyperactive in vitro, in cardiomyocyte co-cultures, and in animal models. We report reduced norepinephrine transporter expression, decreased intracellular norepinephrine (NE), decreased NE re-uptake, and excessive extracellular NE in FD symNs. SymN hyperactivity is not a direct ELP1 mutation result, but may connect to NET via RAB proteins. We found that candidate drugs lowered hyperactivity independent of ELP1 modulation. Our findings may have implications for other symN disorders and may allow future drug testing and discovery.
Description
Keywords
Familial dysautonomia, norepinephrine transporter, sympathetic hyperactivity
Citation
Wu, HF., Yu, W., Saito-Diaz, K. et al. Norepinephrine transporter defects lead to sympathetic hyperactivity in Familial Dysautonomia models. Nat Commun 13, 7032 (2022). https://doi.org/10.1038/s41467-022-34811-7
Collections
Endorsement
Review
Supplemented By
Referenced By
Creative Commons license
Except where otherwised noted, this item's license is described as cc-by