ArticleThe Journal of biological chemistry
Misfolding, altered membrane distributions, and the unfolded protein response contribute to pathogenicity differences in Na,K-ATPase ATP1A3 mutations.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 30 citations in OpenAlex.
- Mechanism of Rescue of NaInternational journal of molecular sciences · 2026Article
- Active conformations of neuronal NaNature communications · 2026Article
- Functional impact of the ATP1A3-p.A813V variant: insights into a calcium-driven hyperexcitability cascade in rapid-onset dystonia-Parkinsonism.Journal of translational medicine · 2026Article
- Caenorhabditis elegans models of alternating hemiplegia of childhood have dominant neuromuscular junction defects.Disease models & mechanisms · 2026Article
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- Natural History of Alternating Hemiplegia of Childhood: Vulnerabilities in Early Childhood and Predictive Factors for Long-Term Outcomes.Annals of the Child Neurology Society · 2025Article
- The Quaternary Structure of the Sodium Pump Regulatory Complex Is Altered by Mutations of a Site Associated with Familial Hemiplegic Migraine.Molecular neurobiology · 2025Article
- Alternating hemiplegia of childhood associated mutations in Atp1a3 reveal diverse neurological alterations in mice.Neurobiology of disease · 2025Article
- Striatal cell-type-specific molecular signatures reveal potential therapeutic targets in a model of dystonia.Neurobiology of disease · 2025Article
- In silico studies provide new structural insights into trans-dimerization of β1 and β2 subunits of the Na+, K+-ATPase.PloS one · 2025Article
- Phenotype Distinctions in Mice Deficient in the Neuron-Specific α3 Subunit of Na,K-ATPase:eNeuro · 2024Article
- Na,K-ATPase Expression Can Be Limited Post-Transcriptionally: A Test of the Role of the Beta Subunit, and a Review of Evidence.International journal of molecular sciences · 2024Review
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- ATP1A3 regulates protein synthesis for mitochondrial stability under heat stress.Disease models & mechanisms · 2024Article
- Ectopic HCN4 Provides a Target Biomarker for the Genetic Spectrum of mTORopathies.Neurology. Genetics · 2024Article
- Article
- ATP1A1-linked diseases require a malfunctioning protein product from one allele.Biochimica et biophysica acta. Molecular cell research · 2024Article
- Mechanisms underlying phenotypic variation in neurogenetic disorders.Nature reviews. Neurology · 2023Review
- Pathological implications of cellular stress in cardiovascular diseases.The international journal of biochemistry & cell biology · 2023Review
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4 authors at 2 institutions in 1 country.
Funding
Abstract
Missense mutations in ATP1A3, the α3 isoform of Na,K-ATPase, cause neurological phenotypes that differ greatly in symptoms and severity. A mechanistic basis for differences is lacking, but reduction of activity alone cannot explain them. Isogenic cell lines with endogenous α1 and inducible exogenous α3 were constructed to compare mutation properties. Na,K-ATPase is made in the endoplasmic reticulum (ER), but the glycan-free catalytic α subunit complexes with glycosylated β subunit in the ER to proceed through Golgi and post-Golgi trafficking. We previously observed classic evidence of protein misfolding in mutations with severe phenotypes: differences in ER retention of endogenous β1 subunit, impaired trafficking of α3, and cytopathology, suggesting that they misfold during biosynthesis. Here we tested two mutations associated with different phenotypes: D923N, which has a median age of onset of hypotonia or dystonia at 3 years, and L924P, with severe infantile epilepsy and profound impairment. Misfolding during biosynthesis in the ER activates the unfolded protein response, a multiarmed program that enhances protein folding capacity, and if that fails, triggers apoptosis. L924P showed more nascent protein retention in ER than D923N; more ER-associated degradation of α3 (ERAD); larger differences in Na,K-ATPase subunit distributions among subcellular fractions; and greater inactivation of eIF2α, a major defensive step of the unfolded protein response. In L924P there was also altered subcellular distribution of endogenous α1 subunit, analogous to a dominant negative effect. Both mutations showed pro-apoptotic sensitization by reduced phosphorylation of BAD. Encouragingly, however, 4-phenylbutyrate, a pharmacological corrector, reduced L924P ER retention, increased α3 expression, and restored morphology.
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