PUBLICATION
Functional impact of the ATP1A3-p.A813V variant: insights into a calcium-driven hyperexcitability cascade in rapid-onset dystonia-Parkinsonism
- Authors
- Lim, S.M., Kim, S., Park, J., Kim, Y.E., Na, O.C., Nahm, M., Noh, M.Y., Oh, K.W., Ki, C.S., Shin, W.H., Park, H.C., Kim, S.H.
- ID
- ZDB-PUB-260512-24
- Date
- 2026
- Source
- Journal of translational medicine : (Journal)
- Registered Authors
- Park, Hae-Chul
- Keywords
- ATP1A3, Calcium dysregulation, Induced neurons, Neurodegeneration, Neuronal hyperexcitability, Rapid-onset dystonia-parkinsonism, Transmembrane hydration, Zebrafish
- MeSH Terms
- none
- PubMed
- 42116168 Full text @ J Transl Med
Citation
Lim, S.M., Kim, S., Park, J., Kim, Y.E., Na, O.C., Nahm, M., Noh, M.Y., Oh, K.W., Ki, C.S., Shin, W.H., Park, H.C., Kim, S.H. (2026) Functional impact of the ATP1A3-p.A813V variant: insights into a calcium-driven hyperexcitability cascade in rapid-onset dystonia-Parkinsonism. Journal of translational medicine. :.
Abstract
Background Mutations in the neuronal Na+/K+-ATPase subunit ATP1A3 are linked to a spectrum of neurological disorders, including rapid-onset dystonia-parkinsonism (RDP), yet their pathogenic mechanisms remain incompletely understood. We describe the complex clinical characteristics of a patient with early-onset movement disorders and a likely pathogenic de novo variant in ATP1A3(c·2483C>T, p.A813V).
Methods We identified a de novo heterozygous ATP1A3 p.A813V variant in a patient with clinically confirmed RDP and employed an integrative approach combining molecular dynamics (MD) simulations, zebrafish models, and patient-derived induced neurons (iNeurons) to delineate its pathogenesis.
Results MD simulations revealed that the p.A813V substitution structurally distorts transmembrane helix packing, reduces structural stability, and diminishes water accessibility at the cation-binding site, predicting impaired Na+/K+-ATPase function. In vivo, atp1a3b knockout zebrafish developed pronounced neuronal hyperexcitability-reflected by elevated c-fos and pERK expression-that emerged before overt neurodegeneration, motor axonopathy, and neuromuscular junction defects. Complementarily, neurons expressing ATP1A3-p.A813V displayed significantly prolonged calcium transient decay times, suggesting a potential mechanism of altered Ca2+ handling and delayed clearance mechanisms compatible with ATP1A3 dysfunction. Consistent with these findings, patient-derived iNeurons exhibited markedly reduced ATP1A3 protein abundance and Na+/K+-ATPase activity.
Conclusions Together, these findings lead us to propose a mechanistic model in which ATP1A3 dysfunction disrupts Ca2+ homeostasis, triggers neuronal hyperexcitability, and culminates in progressive neurodegeneration. This work provides a molecular and functional framework for targeting ionic and calcium homeostasis as a promising therapeutic strategy for ATP1A3-related disorders.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping