Neuronal modeling of alternating hemiplegia of childhood reveals transcriptional compensation and replicates a trigger-induced phenotype.

Autor: Snow JP; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA., Westlake G; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA., Klofas LK; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA., Jeon S; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA., Armstrong LC; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA., Swoboda KJ; Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., George AL Jr; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Ess KC; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA. Electronic address: kevin.ess@vumc.org.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2020 Jul; Vol. 141, pp. 104881. Date of Electronic Publication: 2020 Apr 27.
DOI: 10.1016/j.nbd.2020.104881
Abstrakt: Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disease caused by heterozygous de novo missense mutations in the ATP1A3 gene that encodes the neuronal specific α3 subunit of the Na,K-ATPase (NKA) pump. Mechanisms underlying patient episodes including environmental triggers remain poorly understood, and there are no empirically proven treatments for AHC. In this study, we generated patient-specific induced pluripotent stem cells (iPSCs) and isogenic controls for the E815K ATP1A3 mutation that causes the most phenotypically severe form of AHC. Using an in vitro iPSC-derived cortical neuron disease model, we found elevated levels of ATP1A3 mRNA in AHC lines compared to controls, without significant perturbations in protein expression. Microelectrode array analyses demonstrated that in cortical neuronal cultures, ATP1A3 +/E815K iPSC-derived neurons displayed less overall activity than neurons differentiated from isogenic mutation-corrected and unrelated control cell lines. However, induction of cellular stress by elevated temperature revealed a hyperactivity phenotype following heat stress in ATP1A3 +/E815K neurons compared to control lines. Treatment with flunarizine, a drug commonly used to prevent AHC episodes, did not impact this stress-triggered phenotype. These findings support the use of iPSC-derived neuronal cultures for studying complex neurodevelopmental conditions such as AHC and provide a platform for mechanistic discovery in a human disease model.
Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare.
(Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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