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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.

Original publication

DOI

10.1371/journal.pgen.1006763

Type

Journal article

Journal

PLoS Genet

Publication Date

05/2017

Volume

13

Keywords

Action Potentials, Animals, Dystonic Disorders, Hemiplegia, Heterozygote, Hypothermia, Mice, Mice, Inbred C57BL, Muscle Contraction, Mutation, Parkinson Disease, Purkinje Cells, Sodium, Sodium-Potassium-Exchanging ATPase, Xenopus