Differential Expression of the β3 Subunit of Voltage-Gated Ca 2+ Channel in Mesial Temporal Lobe Epilepsy.

Autor: Kjær C; Biomedical Laboratory Science, Department of Technology, Faculty of Health and Technology, University College Copenhagen, Sigurdsgade 26, 1St, 2200, Copenhagen, Denmark. chkj@kp.dk.; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark. chkj@kp.dk., Palasca O; Disease Systems Biology Program, Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark., Barzaghi G; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark.; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.; Faculty of Biosciences, Collaboration for Joint PhD Degree Between EMBL and Heidelberg University, Heidelberg, Germany., Bak LK; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark.; Dept. of Clinical Biochemistry, 2600, RigshospitaletCopenhagen, Denmark., Durhuus RKJ; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark.; Specific Pharma A/S, Borgmester Christiansens Gade 40, 2450, Copenhagen, SV, Denmark., Jakobsen E; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark.; Takeda Pharma A/S, Delta Park 45, 2665, Vallensbaek Strand, Denmark., Pedersen L; Biomedical Laboratory Science, Department of Technology, Faculty of Health and Technology, University College Copenhagen, Sigurdsgade 26, 1St, 2200, Copenhagen, Denmark.; Dept. of Clinical Biochemistry, 2600, RigshospitaletCopenhagen, Denmark., Bartels ED; Dept. of Clinical Biochemistry, 2600, RigshospitaletCopenhagen, Denmark.; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark., Woldbye DPD; Department of Neuroscience, University of Copenhagen, 2200, Copenhagen, Denmark., Pinborg LH; Epilepsy Clinic & Neurobiology Research Unit, Copenhagen University Hospital, University of Copenhagen, 2100, Copenhagen, Denmark., Jensen LJ; Disease Systems Biology Program, Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
Jazyk: angličtina
Zdroj: Molecular neurobiology [Mol Neurobiol] 2023 Oct; Vol. 60 (10), pp. 5755-5769. Date of Electronic Publication: 2023 Jun 21.
DOI: 10.1007/s12035-023-03426-4
Abstrakt: 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 Ca 2+ channel subunit, was significantly regulated in mTLE at both mRNA and protein level. Considering the key role of Ca 2+ 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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