@article{97ba39741c4b45e8911c9f75d7edd9e7,
title = "A Drosophila Model of Essential Tremor",
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.",
author = "Philip Smith and Ronald Arias and Shilpa Sonti and Zagaa Odgerel and Ismael Santa-Maria and McCabe, {Brian D.} and Krasimira Tsaneva-Atanasova and Louis, {Elan D.} and Hodge, {James J.L.} and Clark, {Lorraine N.}",
note = "Funding Information: This work was supported by a grant from the National Institutes of Health, R01NS073872, to L.N.C and E.D.L. The electrophysiology was supported by a grant from the Biotechnology and Biological Sciences Research Council South West Biosciences, United Kingdom, DTP BB/J014400/1 to J.J.L.H. K.T.-A. gratefully acknowledges the financial support of the Engineering and Physical Sciences Research Council via Grant No. EP/N014391/1. Funding Information: Cloning, mutagenesis and generation of hKv9.2 transgenic Drosophila lines was performed by R.A., L.N.C. and B.D.M. Western blot analysis was performed by S.S., L.N.C. and I.S.-M. Phenotyping and behavioral assays including locomotor assays, lifespan assays, anesthetization induced leg shaking and wing scissoring behavior, and abnormal wing posture analyses was performed by R.A., L.N.C., I.S-M., B.D.M., Z.O. and E.D.L. Electrophysiology and circadian rhythm and sleep behavioral analysis was performed by P.S. and J.J.L.H. Computational modeling was performed by P.S. and K.T-A. Statistical analyses was performed by L.N.C., P.S., J.J.L.H. and K.T-A. L.N.C., B.D.M., J.J.L.H. and K.T.-A. designed the study and wrote the paper. All authors discussed the results and provided critical evaluation and comments on the manuscript. Funding for the study was provided by L.N.C., E.D.L., J.J.L.H., and K.T-A.",
year = "2018",
month = dec,
day = "1",
doi = "10.1038/s41598-018-25949-w",
language = "English (US)",
volume = "8",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",
}