Format

Send to

Choose Destination
Sci Rep. 2018 May 16;8(1):7664. doi: 10.1038/s41598-018-25949-w.

A Drosophila Model of Essential Tremor.

Author information

1
School of Physiology, Pharmacology and Neuroscience, University of Bristol, University Walk, Bristol, BS8 1TD, UK.
2
Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA.
3
Brain Mind Institute, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
4
Department of Mathematics and Living Systems Institute, University of Exeter, Stocker Road, Exeter, EX4 4QD, UK.
5
EPSRC Centre for Predictive Modelling in Healthcare, University of Exeter, Exeter, EX4 4QJ, UK.
6
Department of Neurology, Yale School of Medicine, Yale University, New Haven, CT, 06520, USA.
7
Center for Neuroepidemiology and Clinical Neurological Research, Yale School of Medicine, Yale University, New Haven, CT, 06520, USA.
8
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, 06520, USA.
9
School of Physiology, Pharmacology and Neuroscience, University of Bristol, University Walk, Bristol, BS8 1TD, UK. james.hodge@bristol.ac.uk.
10
Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA. lc654@columbia.edu.
11
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA. lc654@columbia.edu.

Abstract

Essential Tremor (ET) is one of the most common neurological diseases, with an estimated 7 million affected individuals in the US; the pathophysiology of the disorder is poorly understood. Recently, we identified a mutation (KCNS2 (Kv9.2), c.1137 T > A, p.(D379E) in an electrically silent voltage-gated K+ channel α-subunit, Kv9.2, in a family with ET, that modulates the activity of Kv2 channels. We have produced transgenic Drosophila lines that express either the human wild type Kv9.2 (hKv9.2) or the ET causing mutant Kv9.2 (hKv9.2-D379E) subunit in all neurons. We show that the hKv9.2 subunit modulates activity of endogenous Drosophila K+ channel Shab. The mutant hKv9.2-D379E subunit showed significantly higher levels of Shab inactivation and a higher frequency of spontaneous firing rate consistent with neuronal hyperexcitibility. We also observed behavioral manifestations of nervous system dysfunction including effects on night time activity and sleep. This functional data further supports the pathogenicity of the KCNS2 (p.D379E) mutation, consistent with our prior observations including co-segregation with ET in a family, a likely pathogenic change in the channel pore domain and absence from population databases. The Drosophila hKv9.2 transgenic model recapitulates several features of ET and may be employed to advance our understanding of ET disease pathogenesis.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center