High-throughput LC-MS/MS proteomic analysis of a mouse model of mesiotemporal lobe epilepsy predicts microglial activation underlying disease development

Bitsika, V., Duveau, V., Simon-Areces, J., Mullen, W. , Roucard, C., Makridakis, M., Mermelekas, G., Savvopoulos, P., Depaulis, A. and Vlahou, A. (2016) High-throughput LC-MS/MS proteomic analysis of a mouse model of mesiotemporal lobe epilepsy predicts microglial activation underlying disease development. Journal of Proteome Research, 15(5), pp. 1546-1562. (doi: 10.1021/acs.jproteome.6b00003) (PMID:27057777)

Abstract

Uncovering the molecular mechanisms of mesiotemporal lobe epilepsy (MTLE) is critical to identify therapeutic targets. In this study, we performed global protein expression analysis of a kainic acid (KA) MTLE mouse model at various time-points (1, 3, and 30 days post-KA injection -dpi), representing specific stages of the syndrome. High-resolution liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS), in combination with label-free protein quantification using three processing approaches for quantification, was applied. Following comparison of KA versus NaCl-injected mice, 22, 53, and 175 proteins were differentially (statistically significant) expressed at 1, 3 and 30dpi, respectively, according to all three quantification approaches. Selected findings were confirmed by multiple reaction monitoring LC–MS/MS. As a positive control, the astrocyte marker GFAP was found to be upregulated (3dpi: 1.9 fold; 30dpi: 12.5 fold), also verified by IHC. The results collectively suggest that impairment in synaptic transmission occurs even right after initial status epilepticus (1dpi), with neurodegeneration becoming more extensive during epileptogenesis (3dpi) and sustained at the chronic phase (30dpi), where also extensive glial- and astrocyte-mediated inflammation is evident. This molecular profile is in line with observed phenotypic changes in human MTLE, providing the basis for future studies on new molecular targets for the disease.

• Item Type: Articles
• Additional Information: VB, VD, JSA, CR, MM, GM, PS, AD and AV received funding from the European Community's Framework program Neurinox (Health-F2-2011-278611). WM received institutional funds.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Mullen, Dr Bill
• Authors: Bitsika, V., Duveau, V., Simon-Areces, J., Mullen, W., Roucard, C., Makridakis, M., Mermelekas, G., Savvopoulos, P., Depaulis, A., and Vlahou, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Journal of Proteome Research
• Publisher: American Chemical Society
• ISSN: 1535-3893
• ISSN (Online): 1535-3907
• Published Online: 08 April 2016
• Copyright Holders: Copyright © 2016 American Chemical Society
• First Published: First published in Journal of Proteome Research 15(5): 1546-1562
• Publisher Policy: Reproduced in accordance with the publisher copyright policy