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PLoS Genet. 2017 May 4;13(5):e1006763. doi: 10.1371/journal.pgen.1006763. eCollection 2017 May.

Hypothermia-induced dystonia and abnormal cerebellar activity in a mouse model with a single disease-mutation in the sodium-potassium pump.

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Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Centre for Membrane Pumps in Cells and Disease-PUMPKIN, Danish National Research Foundation, Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, Denmark.
Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America.
The Laboratory of Cardiac/Membrane Physiology, The Rockefeller University, New York, New York, United States of America.
Aarhus Institute of Advanced Studies (AIAS), Aarhus University, Aarhus C, Denmark.
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.


Mutations in the neuron-specific α3 isoform of the Na+/K+-ATPase are found in patients suffering from Rapid onset Dystonia Parkinsonism and Alternating Hemiplegia of Childhood, two closely related movement disorders. We show that mice harboring a heterozygous hot spot disease mutation, D801Y (α3+/D801Y), suffer abrupt hypothermia-induced dystonia identified by electromyographic recordings. Single-neuron in vivo recordings in awake α3+/D801Y mice revealed irregular firing of Purkinje cells and their synaptic targets, the deep cerebellar nuclei neurons, which was further exacerbated during dystonia and evolved into abnormal high-frequency burst-like firing. Biophysically, we show that the D-to-Y mutation abolished pump-mediated Na+/K+ exchange, but allowed the pumps to bind Na+ and become phosphorylated. These findings implicate aberrant cerebellar activity in α3 isoform-related dystonia and add to the functional understanding of the scarce and severe mutations in the α3 isoform Na+/K+-ATPase.

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