Reference - Detail
| RRC ID | 89876 |
|---|---|
| Author | Lim SM, Kim S, Park J, Kim YE, Na OC, Nahm M, Noh MY, Oh KW, Ki CS, Shin WH, Park HC, Kim SH. |
| Title | Functional impact of the ATP1A3-p.A813V variant: insights into a calcium-driven hyperexcitability cascade in rapid-onset dystonia-Parkinsonism. |
| Journal | J Transl Med |
| 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·2438C>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. |
| Volume | 24(1) |
| Published | 2026-5-11 |
| DOI | 10.1186/s12967-026-08203-0 |
| PII | 10.1186/s12967-026-08203-0 |
| PMID | 42116168 |
| PMC | PMC13173752 |
| MeSH | Animals Calcium* / metabolism Dystonia* / genetics Dystonia* / physiopathology Dystonic Disorders* / genetics Dystonic Disorders* / physiopathology Female Humans Male Molecular Dynamics Simulation Mutation* / genetics Neurons / metabolism Neurons / pathology Parkinsonian Disorders* / genetics Parkinsonian Disorders* / physiopathology Sodium-Potassium-Exchanging ATPase* / chemistry Sodium-Potassium-Exchanging ATPase* / genetics Sodium-Potassium-Exchanging ATPase* / metabolism Zebrafish |
| Resource | |
| Zebrafish | UAS:GFP, UAS:GCaMP6s |