Alternating hemiplegia of childhood associated mutations in Atp1a3 reveal diverse neurological alterations in mice.

Authors

Markus Terrey, The Jackson LaboratoryFollow
Georgii Krivoshein
Scott I Adamson
Elena Arystarkhova
Laura C. Anderson, The Jackson LaboratoryFollow
John Szwec, The Jackson LaboratoryFollow
Shelby McKee, The Jackson LaboratoryFollow
Holly Jones, The Jackson LaboratoryFollow
Sara Perkins, The Jackson LaboratoryFollow
Vijay Selvam, The Jackson LaboratoryFollow
Pierre-Alexandre Piec, The Jackson LaboratoryFollow
Dweet Chhaya, The Jackson LaboratoryFollow
Ari Dehn, The Jackson LaboratoryFollow
Aamir Zuberi, The Jackson LaboratoryFollow
Stephen A Murray, The Jackson LaboratoryFollow
Natalia S Morsci
Kathleen J Sweadner
David A Knowles
Else A Tolner
Arn M J M van den Maagdenberg
Cathleen Lutz, The Jackson LaboratoryFollow

Document Type

Article

Publication Date

8-1-2025

Original Citation

Terrey M, Krivoshein G, Adamson S, Arystarkhova E, Anderson LC, Szwec J, McKee S, Jones H, Perkins S, Selvam V, Piec P, Chhaya D, Dehn A, Zuberi A, Murray S, Morsci N, Sweadner K, Knowles D, Tolner E, van den Maagdenberg A, Lutz C. Alternating hemiplegia of childhood associated mutations in Atp1a3 reveal diverse neurological alterations in mice. Neurobiol Dis. 2025;212:106954.

Keywords

JMG, SS1, Animals, Sodium-Potassium-Exchanging ATPase, Hemiplegia, Mice, Mutation, Disease Models, Animal, Male, Female, Mice, Inbred C57BL

JAX Source

Neurobiol Dis. 2025;212:106954.

ISSN

1095-953X

PMID

40381892

DOI

https://doi.org/10.1016/j.nbd.2025.106954

Abstract

Pathogenic variants in the neuronal Na⁺/K⁺ ATPase transmembrane ion transporter (ATP1A3) cause a spectrum of neurological disorders including alternating hemiplegia of childhood (AHC). The most common de novo pathogenic variants in AHC are p.D801N (∼40 % of patients) and p.E815K (∼25 % of patients), which lead to early mortality by spontaneous death in mice. Nevertheless, knowledge of the development of clinically relevant neurological phenotypes without the obstacle of premature death, is critical for the identification of pathophysiological mechanisms and ultimately, for the testing of therapeutic strategies in disease models. Here, we used hybrid vigor attempting to mitigate the fragility of AHC mice and then performed behavioral, electrophysiological, biochemical, and molecular testing to comparatively analyze mice that carry either of the two most common AHC patient observed variants in the Atp1a3 gene. Collectively, our data reveal the presence but also the differential impact of the p.D801N and p.E815K variants on disease relevant alterations such as spontaneous and stress-induced paroxysmal episodes, motor function, behavioral and neurophysiological activity, and neuroinflammation. Our alternate AHC mouse models with their phenotypic deficits open novel avenues for the investigation of disease biology and therapeutic testing for ATP1A3 research.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.