Direct evidence of impaired neuronal Na/K-ATPase pump function in alternating hemiplegia of childhood

Simmons, Christine Q.; Thompson, Christopher H.; Cawthon, Bryan; Westlake, Grant; Swoboda, Kathryn J.; Kiskinis, Evangelos; Ess, Kevin C.; George, Alfred L.

doi:10.1016/j.nbd.2018.03.009

Cited by 23 publications

(15 citation statements)

References 35 publications

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“…Thus, it was reasonable that in RDP, most mutations affected protein expression and cell surface expressions, and in the AHC, an altered activity of the pump could explain the phenotype. 8 Several studies have been conducted to clarify that issue 71,77 and one useful approach was by using induced Pluripotent Stem (iPS) cells. Recently, in a model of iPS cells derived neurons from AHC patients carrying the missense mutation p.Gly947Arg, lower levels of ouabainsensitive outward current (a net outward transport of a Na + ions) have been demonstrated compared to controls.…”

Section: Cellular Studiesmentioning

confidence: 99%

“…Recently, in a model of iPS cells derived neurons from AHC patients carrying the missense mutation p.Gly947Arg, lower levels of ouabainsensitive outward current (a net outward transport of a Na + ions) have been demonstrated compared to controls. 77 Furthermore, as it may be predicted by a lower intracellular K + ion concentration, neurons exhibit a resting membrane potential similar to resting cell with altered excitability, dealing with the hypothesis of a loss of function mechanism. 77 Moreover, in a very recent study (2019), Arystarkhova et al point out that severity of phenotype cannot be explained solely by reduction of pump activity and other cellular mechanisms are hypothesized from experimental data, including misfolding protein at Golgi apparatus level and consequent ratio between good and bad alleles, by competition.…”

Section: Cellular Studiesmentioning

confidence: 99%

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<p>Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations</p>

Capuano¹,

Garone²,

Tiralongo³

et al. 2020

TACG

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Alternating hemiplegia of childhood (AHC) is a rare neurological disorder affecting children with an onset before 18 months. Diagnostic clues include transient episodes of hemiplegia alternating in the laterality or quadriparesis, nystagmus and other paroxysmal attacks as tonic and dystonic spells. Epilepsy is also a common feature. In the past, a great effort has been done to understand the genetic basis of the disease leading to the discovery of mutations in the ATP1A3 gene encoding for the alpha3 subunit of Na + / K + ATPase, a protein already related to another disease named Rapid Onset Dystonia Parkinsonism (RDP). ATP1A3 mutations account for more than 70% of cases of AHC. In particular, three hotspot mutations account for about 60% of all cases, and these data have been confirmed in large population studies. Specifically, the p.Asp801Asn variant has been found to cause 30-43% of all cases, p.Glu815Lys is responsible for 16-35% of cases and p. Gly947Arg accounts for 8-15%. These three mutations are associated with different clinical phenotype in terms of symptoms, severity and prognosis. In vitro and in vivo models reveal that a crucial role of Na + /K + ATPase pump activity emerges in maintaining a correct membrane potential, survival and homeostasis of neurons. Herein, we attempt to summarize all clinical, genetic and molecular aspects of AHC considering ATP1A3 as its primary disease-causing determinant.

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Section: Cellular Studiesmentioning

confidence: 99%

Section: Cellular Studiesmentioning

confidence: 99%

<p>Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations</p>

Capuano¹,

Garone²,

Tiralongo³

et al. 2020

TACG

View full text Add to dashboard Cite

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“…Other studies in the field have demonstrated that these electrophysiological aberrations may be related to intracellular increases in sodium concentration in both the presence of AHC causing mutations and with ion transport inhibition after treatment with pump antagonists (Pivovarov et al, 2018;Tiziano, 2019;Toustrup-Jensen et al, 2014). In collaboration, we recently used iPSC-derived neurons with the G947R mutation to investigate fundamental cellular defects and observed impaired ion pump activity and depolarized resting membrane potentials in AHC mutant neurons (Simmons et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Common AHC-causing mutations in the α3 subunit result in impaired ion transporting ability without impacting protein trafficking to the plasma membrane (Heinzen et al, 2014;Koenderink et al, 2003;. A recent study demonstrated lower pump current and depolarized resting membrane potential in AHC-mutant iPSC-derived excitatory neurons (Simmons et al, 2018), and Drosophila and mouse models of Atp1a3 mutations associated with human disease often replicate trigger-induced symptoms or exacerbation (DeAndrade et al, 2011;Helseth et al, 2018;Holm and Lykke-Hartmann, 2016;Isaksen et al, 2017;Palladino et al, 2003;Sugimoto et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Neuronal Modeling of Alternating Hemiplegia of Childhood Reveals Transcriptional Compensation and Replicates a Trigger-Induced Phenotype

Snow

Westlake

Klofas

et al. 2020

Preprint

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ABSTRACTAlternating 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 a non-significant trend toward 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 lines 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 potential route toward future therapeutic screening and mechanistic discovery in a human disease model.

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“…These diseases include (in approximate order of onset in childhood development): early infantile epileptic encephalopathy (EIEE); alternating hemiplegia of childhood (ACH); cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS); childhood onset schizophrenia (COS); and rapid-onset dystonia-parkinsonism (RDP)(Brashear et al, 1993; Smedemark-Margulies et al, 2016). Variants in ATP1A3 associated with these postnatal diseases are generally categorized as heterozygous loss-of-function single nucleotide variants(Arystarkhova et al, 2019; Holm et al, 2016) which, among other deficits, have been shown to lead to depolarized Vm, such as in neurons from AHC patients(Simmons et al, 2018). During development, bioelectric changes can dramatically alter both intrinsic trajectories of individual cells(Levin et al, 2017) and cortical lamination more broadly(Hurni et al, 2017; Vitali et al, 2018), suggesting that bioelectric alterations in early brain development could in part contribute to subsequent ATP1A3- related neurological disorders.…”

Section: Introductionmentioning

confidence: 99%

Role for the Na⁺/K⁺ ATPase pump alpha 3 (ATP1A3) subunit in folding and lamination of the human neocortex

Smith

Florio

Akula

et al. 2020

Preprint

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Osmotic equilibrium and membrane potential in animal cells depend on concentration gradients of sodium (Na+) and potassium (K+) ions across the plasma membrane, a function that is catalyzed by the Na,K-ATPase alpha subunit. In vertebrates, four paralogous genes, ATP1A1-4, encode distinct alpha subunit isoforms (a1-a4), three of which (a1, a2, a3) are expressed in the brain, and two (a1, a3) predominantly in neurons. The a3 isoform, encoded by ATP1A3, is critical to neuronal physiology, and a growing spectrum of neurological diseases are associated with ATP1A3 pathogenic variants, with ages of onset ranging from early childhood to adulthood. Here, we describe ATP1A3 variants encoding dysfunctional a3 subunits in children affected by polymicrogyria, a developmental malformation of the cerebral cortex characterized by abnormal folding and laminar organization. To gain cell-biological insights into the spatiotemporal dynamics of prenatal ATP1A3 expression, we established a transcriptional atlas of ATP1A3 expression during cortical development using mRNA in situ hybridization and transcriptomic profiling of ~125,000 individual cells with single-cell RNA sequencing (Drop-Seq) from various areas of the midgestational human neocortex. We find that fetal expression of ATP1A3 is restricted to a subset of excitatory neurons carrying transcriptional signatures of neuronal activity and maturation characteristic of the developing subplate. Furthermore, by performing Drop-Seq on ~52,000 nuclei from four different areas of an infant human neocortex, we show that ATP1A3 expression persists throughout early postnatal development, not only within excitatory neurons across all cortical layers, but also and more predominantly in inhibitory neurons, with specific enrichment in fast-spiking basket cells. In addition, we show that ATP1A3 expression, both in fetal and postnatal neurons, tends to be higher in frontal cortical areas than in occipital areas, in a pattern consistent with the rostro-caudal maturation gradient of the human neocortex. Finally, we discover distinct co-expression patterns linking catalytic α subunit isoforms (ATP1A1,2,3) and auxiliary isoforms (ATP1B1,2,3), suggesting the ATPase pump may form non-redundant, cell-type specific α-β combinations. Together, the importance of the developmental phenotypes and dynamic expression patterns of ATP1A3 point to a key role for a3 in the development and function of human cortex.

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Direct evidence of impaired neuronal Na/K-ATPase pump function in alternating hemiplegia of childhood

Cited by 23 publications

References 35 publications

<p>Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations</p>

<p>Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations</p>

Neuronal Modeling of Alternating Hemiplegia of Childhood Reveals Transcriptional Compensation and Replicates a Trigger-Induced Phenotype

Role for the Na⁺/K⁺ ATPase pump alpha 3 (ATP1A3) subunit in folding and lamination of the human neocortex

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Direct evidence of impaired neuronal Na/K-ATPase pump function in alternating hemiplegia of childhood

Cited by 23 publications

References 35 publications

<p>Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations</p>

<p>Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations</p>

Neuronal Modeling of Alternating Hemiplegia of Childhood Reveals Transcriptional Compensation and Replicates a Trigger-Induced Phenotype

Role for the Na+/K+ ATPase pump alpha 3 (ATP1A3) subunit in folding and lamination of the human neocortex

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Product

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Role for the Na⁺/K⁺ ATPase pump alpha 3 (ATP1A3) subunit in folding and lamination of the human neocortex