Norepinephrine transporter defects lead to sympathetic hyperactivity in Familial Dysautonomia models

Hsueh-Fu Wu, Wenxin Yu, Kenyi Saito-Diaz, Chia-Wei Huang, Joseph Carey, Frances Lefcort, Gerald W. Hart, Hong-Xiang Liu and Nadja Zeltner ()
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Hsueh-Fu Wu: University of Georgia
Wenxin Yu: University of Georgia
Kenyi Saito-Diaz: University of Georgia
Chia-Wei Huang: University of Georgia
Joseph Carey: Montana State University
Frances Lefcort: Montana State University
Gerald W. Hart: University of Georgia
Hong-Xiang Liu: University of Georgia
Nadja Zeltner: University of Georgia

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34811-7

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