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Wang, Yundi

University of British Columbia

Preclinical drug discovery relies on the identification of appropriate target compounds and usage of effective animal model screening tests. In this work excitability across systems as well as spatial and temporal scales were evaluated to understand long QT syndrome (LQTS) therapeutic targets and develop a behavioral assay that could sensitively characterize motor phenotype onset in a Huntington Disease (HD) mouse model. Case I: The pairing of the tetrameric voltage-gated potassium channel, KCNQ1, with an accessory β-subunit, KCNE1, gives rise to the slow delayed cardiac rectifier current (IKs), known to play an important role in the physiological shortening of the cardiac action potential. With loss-of-function mutations in both subunits found to be associated with LQTS, enhancing IKs has been identified as a therapeutic approach. Here, the NSAID, mefenamic acid, was found to dose- and rate-dependently activate IKs. More KCNE1-saturated IKs channel complexes had a greater response to mefenamic acid treatment. KCNE1 residue K41 was identified as critical for mefenamic acid action, suggesting a potential binding site. Case II: HD is a dominantly inherited neurodegenerative disease with characteristic motor symptoms. Animal models with increasingly better face and construct validity have been developed to understand HD pathophysiology. Although HD gross motor defects have been extensively characterized, less is known about forelimb motor deficits. Using a high-throughput alternating reward/non-reward water-reaching task, HD forelimb movement defects and associated aberrant cortical activity were examined. HD heterozygous-zQ175 mice displayed an event sequence defect at ~5.5 months with progressive forelimb deficits starting at ~6 months. Cortical activity associated with water-reaching increased over time in HD but not wildtype mice. Gross motor defects characterized using the tapered beam and rotarod tasks, as well as post-hoc striatal immunostaining, confirmed HD pathology at ~8 months. Overall, at the nanoscale level, a biophysical and pharmacological characterization of mefenamic acid’s effect on IKs highlighted a binding site and the potential of the NSAID to act as a precursor compound for LQTS therapeutic development. At the mesoscale level, a water-reaching task was developed and used to characterize HD phenotype demonstrating the potential of the behavioral task to examine therapeutic efficacy and intervention windows.

Text

2023-04-13

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/84190

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/