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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.

Author information

1
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
2
Centre for Membrane Pumps in Cells and Disease-PUMPKIN, Danish National Research Foundation, Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, Denmark.
3
Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America.
4
The Laboratory of Cardiac/Membrane Physiology, The Rockefeller University, New York, New York, United States of America.
5
Aarhus Institute of Advanced Studies (AIAS), Aarhus University, Aarhus C, Denmark.
6
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

Abstract

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.

PMID:
28472154
PMCID:
PMC5436892
DOI:
10.1371/journal.pgen.1006763
[Indexed for MEDLINE]
Free PMC Article

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