A Drosophila Model of Essential Tremor

Scientific Reports
Philip SmithLorraine N Clark

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 Drosoph...Continue Reading

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Citations

May 28, 2019·The Cerebellum·Sheng-Han KuoRodger J Elble
May 30, 2019·Annals of Clinical and Translational Neurology·Yi-Lin OngEng-King Tan
Dec 11, 2019·Expert Reviews in Molecular Medicine·Hao DengJoseph Jankovic
Jun 27, 2019·Neurological Research·Sibel GülerNezih Dağdeviren
Dec 2, 2020·International Journal of Molecular Sciences·Valentina Pallottini, Frank W Pfrieger
Nov 11, 2019·Neuroscience Letters·Regina T MartuscelloPhyllis L Faust

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Methods Mentioned

BETA
transgenic

Software Mentioned

Prism
pClamp10 Clampex
GraphPad
pClamp10 Clampfit
Matlab

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