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dc.contributor.authorWu, Hsueh-Fu
dc.contributor.authorYu, Wenxin
dc.contributor.authorSaito-Diaz, Kenyi
dc.contributor.authorHuang, Chia-Wei
dc.contributor.authorCarey, Joseph
dc.contributor.authorLefcort, Frances
dc.contributor.authorHart, Gerald W.
dc.contributor.authorLiu, Hong-Xiang
dc.contributor.authorZeltner, Nadja
dc.identifier.citationWu, HF., Yu, W., Saito-Diaz, K. et al. Norepinephrine transporter defects lead to sympathetic hyperactivity in Familial Dysautonomia models. Nat Commun 13, 7032 (2022).
dc.description.abstractFamilial 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.en_US
dc.publisherSpringer Science and Business Media LLCen_US
dc.subjectFamilial dysautonomiaen_US
dc.subjectnorepinephrine transporteren_US
dc.subjectsympathetic hyperactivityen_US
dc.titleNorepinephrine transporter defects lead to sympathetic hyperactivity in Familial Dysautonomia modelsen_US
mus.citation.journaltitleNature Communicationsen_US
mus.relation.collegeCollege of Agricultureen_US
mus.relation.departmentMicrobiology & Immunology.en_US
mus.relation.universityMontana State University - Bozemanen_US

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