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A Drosophila model of generalised epilepsy and paroxysmal dyskinesia: generation, characterisation, and functional analysis

Kratschmer, Patrick; (2019) A Drosophila model of generalised epilepsy and paroxysmal dyskinesia: generation, characterisation, and functional analysis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Generalised epilepsy and paroxysmal dyskinesia (GEPD) patients present with epilepsy (absence- and generalised tonic-clonic seizures), paroxysmal dyskinesia (non-kinesigenic), or a combination thereof. GEPD is linked to a missense mutation (D434G) in KCNMA1, which encodes the alpha-subunit of the BK channel, a Ca2+- and voltage-activated K+ channel. Previous studies have demonstrated that this mutation causes a gain of BK channel function by potentiating the allosteric coupling between Ca2+ binding and channel opening. Due to the role of BK channels in action potential repolarisation, it has been hypothesised that the D434G mutation narrows action potential width and increases neuronal firing frequencies, leading to seizures and dyskinetic attacks. // However, BK channels are expressed broadly throughout the human body, including various extra-neuronal tissues, and, on a subcellular level, localise not only to the plasma membrane but also to various intracellular organelles. Due to this pleiotropy, the organismal effects of the D434G mutation remain unclear. In this thesis, I present the generation, characterisation, and functional analysis of a novel knock-in fly model carrying the D434G-equivalent E366G mutation in slowpoke (slo), the Drosophila orthologue of KCNMA1 – this novel slo allele is termed sloE366G. // Evidence is provided that the E366G mutation increases the Ca2+-sensitivity of Slo channels ex vivo. Moreover, sloE366G/+ animals exhibit a severe decrease in locomotion and altered action selection, phenotypes that correlate with aberrant motoneuron activity, as shown via electrophysiology and live optical imaging. Using a genetic approach, I demonstrate that cholinergic neurons mediate this locomotor defect. Further, via RNA-sequencing I provide evidence that sloE366G/+ flies exhibit altered metabolic-, redox-, and immune function, and that the stress-responsive transcription factor foxo genetically interacts with sloE366G. Together, these data suggest a pathogenic locus for GEPD and define molecular pathways involved in GEPD pathogenesis.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: A Drosophila model of generalised epilepsy and paroxysmal dyskinesia: generation, characterisation, and functional analysis
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
URI: https://discovery.ucl.ac.uk/id/eprint/10082177
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