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

Toke Jost Isaksen,Ariel Vitenzon,David C Gadsby,Lieke Kros,Kamran Khodakhah,Thomas Hellesøe Holm,Karin Lykke-Hartmann,Natascia Vedovato,Steven Petrou

doi:10.1371/journal.pgen.1006763

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.

Highlights

Dystonia is a movement disorder characterized by involuntary sustained or repetitive muscle contractions, causing twisting movements and abnormal postures [1, 2]
To elucidate the disease-specific pathophysiology, we examined a mouse model harboring the mutation D801Y, which was originally found in a patient with Rapid onset Dystonia Parkinsonism, but recently, in a patient with Alternating Hemiplegia of Childhood
We found that this model exhibited motor deficits and developed dystonia when exposed to a drop in body temperature

Summary

Introduction

Dystonia is a movement disorder characterized by involuntary sustained or repetitive muscle contractions, causing twisting movements and abnormal postures [1, 2]. It is usually caused by head injuries, drug side effects, metabolic insult, or genetic alterations, and is thought to involve the neuroanatomic circuitry of the basal ganglia, sensorimotor cortex, brainstem, and cerebellum [3]. Several mutations in the ATP1A3 (DYT12) gene, encoding the neuron-specific α3 isoform of the Na+/K+-ATPase, can cause rapid-onset dystonia-parkinsonism (RDP) characterized by an abrupt onset of dystonia and parkinsonian motor-related features [5], or alternating hemiplegia of childhood (AHC) characterized by fluctuating spells of tonic, dystonic, hemiplegic and oculomotor abnormalities [6,7,8]. All three ATP1A3 disorders are typically triggered by environmental and/or physiological events such as physical exhaustion, temperature changes, emotional stress, or infections, pointing to a broad spectrum of often distinct, yet overlapping, neurological disorders [10]

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