ATP1A3 dysfunction causes motor hyperexcitability and afterhyperpolarization loss in a dystonia model

Evgeny Akkuratov; Francesca Sorrell; Laurence D Picton; Vasco C. Sousa; Martin Paucar; Daniel Jans; Lill-Britt Svensson; Maria Lindskog; Nicolas Fritz; Thomas Liebmann; Keith Thomas Sillar; Hendrik Rosewich; Per Svenningsson; Hjalmar Brismar; Gareth Brian Miles; Anita Aperia

doi:10.1093/brain/awae373

ATP1A3 dysfunction causes motor hyperexcitability and afterhyperpolarization loss in a dystonia model

Evgeny Akkuratov, Francesca Sorrell, Laurence D Picton, Vasco C. Sousa, Martin Paucar, Daniel Jans, Lill-Britt Svensson, Maria Lindskog, Nicolas Fritz, Thomas Liebmann, Keith Thomas Sillar, Hendrik Rosewich, Per Svenningsson, Hjalmar Brismar, Gareth Brian Miles^*, Anita Aperia^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Mutations in the gene encoding the alpha3 Na⁺/K⁺-ATPase isoform (ATP1A3) lead to movement disorders that manifest with dystonia, a common neurological symptom with many different origins, but for which the underlying molecular mechanisms remain poorly understood.

We have generated an ATP1A3 mutant mouse that displays motor impairments and a hyperexcitable motor phenotype compatible with dystonia. We show that neurons harboring this mutation are compromised in their ability to extrude raised levels of intracellular sodium, highlighting a profound deficit in neuronal sodium homeostasis. We show that the spinal motor network in ATP1A3 mutant mice has a reduced responsiveness to activity-dependent rises in intracellular sodium and that this is accompanied by loss of the Na⁺/K⁺-ATPase-mediated afterhyperpolarization in motor neurons.

Taken together, our data support that the alpha3 Na⁺/K⁺-ATPase is important for cellular and spinal motor network homeostasis. These insights suggest that it may be useful to consider ways to compensate for this loss of a critical afterhyperpolarization-dependent control of neuronal excitability when developing future therapies for dystonia.

Original language	English
Article number	awae373
Pages (from-to)	1099-1105
Number of pages	7
Journal	Brain
Volume	148
Issue number	4
Early online date	21 Jan 2025
DOIs	https://doi.org/10.1093/brain/awae373
Publication status	Published - 1 Apr 2025

Keywords

Na+/K+-ATPase
Rapid-onset dystonia-parkinsonism
Spinal cord
Motor control
ATP1A3 gene

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Copyright © The Author(s) 2024. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
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Akkuratov, E., Sorrell, F., Picton, L. D., Sousa, V. C., Paucar, M., Jans, D., Svensson, L.-B., Lindskog, M., Fritz, N., Liebmann, T., Sillar, K. T., Rosewich, H., Svenningsson, P., Brismar, H., Miles, G. B., & Aperia, A. (2025). ATP1A3 dysfunction causes motor hyperexcitability and afterhyperpolarization loss in a dystonia model. Brain, 148(4), 1099-1105. Article awae373. https://doi.org/10.1093/brain/awae373

@article{a7a7e5547b0c4fcab517954f9f868153,

title = "ATP1A3 dysfunction causes motor hyperexcitability and afterhyperpolarization loss in a dystonia model",

abstract = "Mutations in the gene encoding the alpha3 Na+/K+-ATPase isoform (ATP1A3) lead to movement disorders that manifest with dystonia, a common neurological symptom with many different origins, but for which the underlying molecular mechanisms remain poorly understood. We have generated an ATP1A3 mutant mouse that displays motor impairments and a hyperexcitable motor phenotype compatible with dystonia. We show that neurons harboring this mutation are compromised in their ability to extrude raised levels of intracellular sodium, highlighting a profound deficit in neuronal sodium homeostasis. We show that the spinal motor network in ATP1A3 mutant mice has a reduced responsiveness to activity-dependent rises in intracellular sodium and that this is accompanied by loss of the Na+/K+-ATPase-mediated afterhyperpolarization in motor neurons. Taken together, our data support that the alpha3 Na+/K+-ATPase is important for cellular and spinal motor network homeostasis. These insights suggest that it may be useful to consider ways to compensate for this loss of a critical afterhyperpolarization-dependent control of neuronal excitability when developing future therapies for dystonia.",

keywords = "Na+/K+-ATPase, Rapid-onset dystonia-parkinsonism, Spinal cord, Motor control, ATP1A3 gene",

author = "Evgeny Akkuratov and Francesca Sorrell and Picton, \{Laurence D\} and Sousa, \{Vasco C.\} and Martin Paucar and Daniel Jans and Lill-Britt Svensson and Maria Lindskog and Nicolas Fritz and Thomas Liebmann and Sillar, \{Keith Thomas\} and Hendrik Rosewich and Per Svenningsson and Hjalmar Brismar and Miles, \{Gareth Brian\} and Anita Aperia",

note = "Funding: Biotechnology and Biological Sciences Research Council (grant number BB/T015705/1), Svenska S{\"a}llskapet f{\"o}r Medicinsk Forskning. ",

year = "2025",

month = apr,

day = "1",

doi = "10.1093/brain/awae373",

language = "English",

volume = "148",

pages = "1099--1105",

journal = "Brain",

issn = "0006-8950",

publisher = "Oxford University Press",

number = "4",

}

Akkuratov, E, Sorrell, F, Picton, LD, Sousa, VC, Paucar, M, Jans, D, Svensson, L-B, Lindskog, M, Fritz, N, Liebmann, T, Sillar, KT, Rosewich, H, Svenningsson, P, Brismar, H, Miles, GB & Aperia, A 2025, 'ATP1A3 dysfunction causes motor hyperexcitability and afterhyperpolarization loss in a dystonia model', Brain, vol. 148, no. 4, awae373, pp. 1099-1105. https://doi.org/10.1093/brain/awae373

TY - JOUR

T1 - ATP1A3 dysfunction causes motor hyperexcitability and afterhyperpolarization loss in a dystonia model

AU - Akkuratov, Evgeny

AU - Sorrell, Francesca

AU - Picton, Laurence D

AU - Sousa, Vasco C.

AU - Paucar, Martin

AU - Jans, Daniel

AU - Svensson, Lill-Britt

AU - Lindskog, Maria

AU - Fritz, Nicolas

AU - Liebmann, Thomas

AU - Sillar, Keith Thomas

AU - Rosewich, Hendrik

AU - Svenningsson, Per

AU - Brismar, Hjalmar

AU - Miles, Gareth Brian

AU - Aperia, Anita

N1 - Funding: Biotechnology and Biological Sciences Research Council (grant number BB/T015705/1), Svenska Sällskapet för Medicinsk Forskning.

PY - 2025/4/1

Y1 - 2025/4/1

N2 - Mutations in the gene encoding the alpha3 Na+/K+-ATPase isoform (ATP1A3) lead to movement disorders that manifest with dystonia, a common neurological symptom with many different origins, but for which the underlying molecular mechanisms remain poorly understood. We have generated an ATP1A3 mutant mouse that displays motor impairments and a hyperexcitable motor phenotype compatible with dystonia. We show that neurons harboring this mutation are compromised in their ability to extrude raised levels of intracellular sodium, highlighting a profound deficit in neuronal sodium homeostasis. We show that the spinal motor network in ATP1A3 mutant mice has a reduced responsiveness to activity-dependent rises in intracellular sodium and that this is accompanied by loss of the Na+/K+-ATPase-mediated afterhyperpolarization in motor neurons. Taken together, our data support that the alpha3 Na+/K+-ATPase is important for cellular and spinal motor network homeostasis. These insights suggest that it may be useful to consider ways to compensate for this loss of a critical afterhyperpolarization-dependent control of neuronal excitability when developing future therapies for dystonia.

AB - Mutations in the gene encoding the alpha3 Na+/K+-ATPase isoform (ATP1A3) lead to movement disorders that manifest with dystonia, a common neurological symptom with many different origins, but for which the underlying molecular mechanisms remain poorly understood. We have generated an ATP1A3 mutant mouse that displays motor impairments and a hyperexcitable motor phenotype compatible with dystonia. We show that neurons harboring this mutation are compromised in their ability to extrude raised levels of intracellular sodium, highlighting a profound deficit in neuronal sodium homeostasis. We show that the spinal motor network in ATP1A3 mutant mice has a reduced responsiveness to activity-dependent rises in intracellular sodium and that this is accompanied by loss of the Na+/K+-ATPase-mediated afterhyperpolarization in motor neurons. Taken together, our data support that the alpha3 Na+/K+-ATPase is important for cellular and spinal motor network homeostasis. These insights suggest that it may be useful to consider ways to compensate for this loss of a critical afterhyperpolarization-dependent control of neuronal excitability when developing future therapies for dystonia.

KW - Na+/K+-ATPase

KW - Rapid-onset dystonia-parkinsonism

KW - Spinal cord

KW - Motor control

KW - ATP1A3 gene

UR - https://www.scopus.com/pages/publications/105002980978

U2 - 10.1093/brain/awae373

DO - 10.1093/brain/awae373

M3 - Article

SN - 0006-8950

VL - 148

SP - 1099

EP - 1105

JO - Brain

JF - Brain

IS - 4

M1 - awae373

ER -

ATP1A3 dysfunction causes motor hyperexcitability and afterhyperpolarization loss in a dystonia model

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Distribution and modulation of dynamic s: Distribution and modulation of dynamic sodium pumps in a spinal motor network

ISSF3 Miles: ISSF3 Miles