TY - JOUR
T1 - Hypothermia-induced dystonia and abnormal cerebellar activity in a mouse model with a single disease-mutation in the sodium-potassium pump
AU - Isaksen, Toke Jost
AU - Kros, Lieke
AU - Vedovato, Natascia
AU - Holm, Thomas Hellesøe
AU - Vitenzon, Ariel
AU - Gadsby, David C.
AU - Khodakhah, Kamran
AU - Lykke-Hartmann, Karin
N1 - Publisher Copyright:
© 2017 Isaksen et al.
PY - 2017/5
Y1 - 2017/5
N2 - Mutations in the neuron-specific α3isoform 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 +/D801Ymice 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 α3isoform-related dystonia and add to the functional understanding of the scarce and severe mutations in the α3isoform Na+/K+-ATPase.
AB - Mutations in the neuron-specific α3isoform 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 +/D801Ymice 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 α3isoform-related dystonia and add to the functional understanding of the scarce and severe mutations in the α3isoform Na+/K+-ATPase.
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U2 - 10.1371/journal.pgen.1006763
DO - 10.1371/journal.pgen.1006763
M3 - Article
C2 - 28472154
AN - SCOPUS:85020203294
SN - 1553-7390
VL - 13
JO - PLoS genetics
JF - PLoS genetics
IS - 5
M1 - e1006763
ER -