Differential Expression of the β3 Subunit of Voltage-Gated Ca2+ Channel in Mesial Temporal Lobe Epilepsy

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Dokumenter

  • Fulltext

    Forlagets udgivne version, 1,97 MB, PDF-dokument

The purpose of this study was to identify and validate new putative lead drug targets in drug-resistant mesial temporal lobe epilepsy (mTLE) starting from differentially expressed genes (DEGs) previously identified in mTLE in humans by transcriptome analysis. We identified consensus DEGs among two independent mTLE transcriptome datasets and assigned them status as “lead target” if they (1) were involved in neuronal excitability, (2) were new in mTLE, and (3) were druggable. For this, we created a consensus DEG network in STRING and annotated it with information from the DISEASES database and the Target Central Resource Database (TCRD). Next, we attempted to validate lead targets using qPCR, immunohistochemistry, and Western blot on hippocampal and temporal lobe neocortical tissue from mTLE patients and non-epilepsy controls, respectively. Here we created a robust, unbiased list of 113 consensus DEGs starting from two lists of 3040 and 5523 mTLE significant DEGs, respectively, and identified five lead targets. Next, we showed that CACNB3, a voltage-gated Ca2+ channel subunit, was significantly regulated in mTLE at both mRNA and protein level. Considering the key role of Ca2+ currents in regulating neuronal excitability, this suggested a role for CACNB3 in seizure generation. This is the first time changes in CACNB3 expression have been associated with drug-resistant epilepsy in humans, and since efficient therapeutic strategies for the treatment of drug-resistant mTLE are lacking, our finding might represent a step toward designing such new treatment strategies.
OriginalsprogEngelsk
TidsskriftMolecular Neurobiology
Vol/bind60
Sider (fra-til)5755–5769
ISSN0893-7648
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
Open access funding provided by University College Copenhagen The Library This work was in part funded by the Novo Nordisk Foundation (NNF14CC0001), the Department of Drug design and Pharmacology, Copenhagen University, the Kirsten and Freddy Johansen’s Foundation, the Medical Doctor Sofus Carl Emil Friis and wife Olga Dorus Friis’ foundation, the P.A. Messerschmidt and Wife’s Foundation and Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of manuscript.

Funding Information:
The authors thank the staff at the Department of Pathology, Aarhus University Hospital, especially biomedical scientist Jeanette Bæhr Georgsen and the staff at the Department of Clinical Biochemistry, Rigshospitalet, especially biomedical scientist Lis Schutt Nielsen. The Human Brain Tissue Bank, Semmelweis University, Budapest (supported by the Hungarian Brain Research Program, grant number 2017-1.2.1-NKP-2017-00002) is greatly acknowledged for their kind donation of brain tissue from non-epilepsy control subjects for this study. We acknowledge the Edinburg Brain Bank and The Netherlands Brain Bank for permitting us to use brain tissue from cases of non-epilepsy control subjects in this study. The London Neurodegenerative Diseases Brain Bank is greatly acknowledged for permitting us to use brain tissue cases of non-epilepsy control subjects in this study. Finally, we acknowledge the Oxford Brain Bank, supported by the Medical Research Council (MRC), the NIHR Oxford Biomedical Research Centre, and the Brains for Dementia Research program, jointly funded by Alzheimer’s Society.

Publisher Copyright:
© 2023, The Author(s).

ID: 358108453