@article{e16dac6761fb4ccc8a493609e1626ecf,
title = "Astrocyte deletion of α2-Na/K ATPase triggers episodic motor paralysis in mice via a metabolic pathway",
abstract = "Familial hemiplegic migraine is an episodic neurological disorder characterized by transient sensory and motor symptoms and signs. Mutations of the ion pump α2-Na/K ATPase cause familial hemiplegic migraine, but the mechanisms by which α2-Na/K ATPase mutations lead to the migraine phenotype remain incompletely understood. Here, we show that mice in which α2-Na/K ATPase is conditionally deleted in astrocytes display episodic paralysis. Functional neuroimaging reveals that conditional α2-Na/K ATPase knockout triggers spontaneous cortical spreading depression events that are associated with EEG low voltage activity events, which correlate with transient motor impairment in these mice. Transcriptomic and metabolomic analyses show that α2-Na/K ATPase loss alters metabolic gene expression with consequent serine and glycine elevation in the brain. A serine- and glycine-free diet rescues the transient motor impairment in conditional α2-Na/K ATPase knockout mice. Together, our findings define a metabolic mechanism regulated by astrocytic α2-Na/K ATPase that triggers episodic motor paralysis in mice.",
author = "Smith, {Sarah E.} and Xiaoying Chen and Brier, {Lindsey M.} and Bumstead, {Jonathan R.} and Rensing, {Nicholas R.} and Ringel, {Alison E.} and Haewon Shin and Anna Oldenborg and Crowley, {Jan R.} and Bice, {Annie R.} and Krikor Dikranian and Ippolito, {Joseph E.} and Haigis, {Marcia C.} and Thomas Papouin and Guoyan Zhao and Michael Wong and Culver, {Joseph P.} and Azad Bonni",
note = "Funding Information: We thank members of the Bonni laboratory for helpful discussions and critical reading of the manuscript, Shakchhi Joshi for assistance with LC–MS studies, and the Genome Technology Access Center (GTAC) and McDonnell Genome Institute (MGI) for sequencing analyses. This work was supported by NIH/NINDS grant NS051255 (A.B.), NIH/NINDS grant NS041021 (A.B.), the Mathers Foundation (A.B.), NIH/NINDS grant F30 NS100217 (S.E.S.), NIH/NIGMS WUSM MSTP grant T32 GM07200 (S.E.S. and L.M.B.), Postdoctoral Fellowship from the American Cancer Society 130373-PF-17-132-01-CCG (A.E.R.), NIH/NICHD grant U54 HD087011 to the Washington University Intellectual and Developmental Disabilities Research Center (IDDRC, M.W. and J.P.C.), NIH/NINDS grant R01 NS056872 (M.W.), The Glenn Foundation for Medical Research (M.C.H.), NIH/NCI grant U54CA224088 (M.C.H), NIH/NINDS grant R01 NS099429 (J.P.C.), NIH/NINDS grant P30 NS098577 (to J.P.C.), NIH/NIGMS grant P41 GM103422 (J.R.C.), NIH/NIDDK grant P30 DK020579 (J.R.C.), and NIH/NIDDK grant P30 DK056341 (J.R.C.). Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2020",
month = dec,
doi = "10.1038/s41467-020-19915-2",
language = "English",
volume = "11",
journal = "Nature Communications",
issn = "2041-1723",
number = "1",
}