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Molecular mechanisms of epileptogenesis
Epilepsy is a severe chronic brain disorder characterized by recurrent seizure activity due to aberrant neuronal network activity. Despite many years of research, the underlying mechanisms that orchestrate seizure activity are still not fully understood. In the last decades, enormous progress has been made in the discovery of epilepsy genes. Our research focuses on understanding the pathophysiological role of such so-called epilepsy genes. By applying a combination of molecular, biochemical and electrophysiological experiments, we expect to improve our understanding of epilepsy pathogenesis. A better understanding of the (dys)functioning of such proteins might open new possibilities for pharmacological intervention, including the design of gene/pathway-specific drugs and the application of disease-preventing strategies.
Dr. Karen M.J. van Loo
kvanlooukaachende
Address
Dept. of Neurology, Section Epileptology
RWTH Aachen University Hospital
Pauwelsstrasse 30
52074 Aachen, Germany
Tel. +49-(0)241- 80-38610
Team
Dr. Karen M.J. van Loo
kvanlooukaachende
Address
Dept. of Neurology, Section Epileptology
RWTH Aachen University Hospital
Pauwelsstrasse 30
52074 Aachen, Germany
Tel. +49-(0)241- 80-38610
Katharina Schmied, Bsc
kschmiedukaachende
Address
Dept. of Neurology, Section Epileptology
University of Aachen
Pauwelsstrasse 30
52074 Aachen, Germany
Sabrina Ingrid Peter, Bsc
sapeterukaachende
Address
Dept. of Neurology, Section Epileptology
University of Aachen
Pauwelsstrasse 30
52074 Aachen, Germany
Birgit Gittel (lead technician)
bgittelukaachende
Address
Dept. of Neurology, Section Epileptology
University of Aachen
Pauwelsstrasse 30
52074 Aachen, Germany
Tel. +49-(0)241-80-38611
Research projects and techniques
Genetic studies have revealed that many susceptibility genes for the epilepsies encode ion channels, including voltage-gated sodium, potassium and calcium channels. Such so-called ion channelopathies might be caused by 1) mutations (genetic epilepsies) or by 2) expression changes (acquired epilepsies). In our group, we analyze how expression changes in ion channel genes are induced and how we can modulate/antagonize such channelopathies.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971179/pdf/fncel-13-00587.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788814/pdf/zns3175.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846312/pdf/ncomms9688.pdf
Viral delivery systems, including Adeno-Associated Viruses and Lentiviruses, are valuable tools for neuroscience research, including epilepsy research. In this project, we design, produce and test viral systems to learn how we can use such approaches for the diagnosis and treatment of epilepsy. By applying such viral systems to organotypic brain slice cultures, we can analyze the molecular and electrophysiological properties at the single cell and at the small network level in mouse and human brain tissue.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8770422/pdf/fnmol-14-667143.pdf
Publications
2024:
Bak A, Koch H, van Loo KMJ, Schmied K, Gittel B, Weber Y, Ort J, Schwarz N, Tauber SC, Wuttke TV, Delev D (2024) Human organotypic brain slice cultures: a detailed and improved protocol for preparation and long-term maintenance. J Neurosci Methods Jan4:110055. Doi: 10.1016/j.jneumeth.2023.110055..
2019 - 2023
Galvis-Montes DS*, van Loo KMJ*, van Waardenberg AJ, Surges R, Schoch S, Becker AJ, Pitsch J (2023) Highly dynamic inflammatory and excitability transcriptional profiles in hippocampal CA1 following status epilepticus. Sci Rep Dec 14;13(1)22187. Doi:10.1038/s41598-023-49310-y.
Gallus M, Roll W, Dik A, Barca C, Zinnhardt B, Hicking G, Mueller C, Naik VN, Anstötz M, Krämer J, Rolfes L, Wachsmuth L, Pitsch J, van Loo KMJ, Räuber S, Okada H, Wimberley C, Strippel C, Golombeck KS, Johnen A, Kovac S, Groß CC, Backhaus P, Seifert R, Lewerenz J, Surges R, Elger CE, Wiendl H, Ruck T, Becker AJ, Faber C, Jacobs AH, Bauer J, Meuth SG, Schäfers M, Melzer N. (2023) Translational imaging of TSPO reveals pronounced innate inflammation in human and murine CD8 T cell-mediated limbic encephalitis. Sci Adv. 2023 Jun 9;9(23):eabq7595. doi: 10.1126/sciadv.abq7595.
Vana NS, van Loo KMJ, van Waardenberg AJ, Tießen M, Cases-Cunillera S, Sun W, Quatraccioni A, Schoch S, Dietrich D. (2023) Early cortical oligodendrocyte precursor cells are transcriptionally distinct and lack synaptic connections. Glia. Sep;71(9):2210-2233. doi: 10.1002/glia.24388
Kyriazi, M., Müller, P., Pitsch, J., van Loo, KMJ, Quatraccioni, A., Opitz, T., Schoch, S., Becker, A.J. and Cases-Cunillera, S. (2022) Neurochemical profile of BRAFV600E/AktT308D/S473D mouse gangliogliomas reveals impaired GABAergic system inhibition. Dev Neurosci.
Van Loo KMJ, Carvill GL, Becker AJ, et al (2022) Epigenetic genes and epilepsy - emerging mechanisms and clinical applications. Nat Rev Neurol 18:530–543. https://doi.org/10.1038/S41582-022-00693-Y
Silvennoinen K, Gawel K, Tsortouktzidis D, Pitsch J, Alhusaini S, van Loo KMJ, et al. (2022) SCN1A overexpression, associated with a genomic region marked by a risk variant for a common epilepsy, raises seizure susceptibility. Acta Neuropathol. May 12. doi: 10.1007/s00401-022-02429-0.
Tsortouktzidis D, Tröscher AR, Schulz H, Opitz T, Schoch S, Becker AJ, van Loo KMJ (2022). A Versatile Clustered Regularly Interspaced Palindromic Repeats Toolbox to Study Neurological CaV3.2 Channelopathies by Promoter-Mediated Transcription Control. Front Mol Neurosci. Jan 6;14:667143. doi: 10.3389/fnmol.2021.667143.
Cases-Cunillera S, van Loo KMJ, Pitsch J, Quatraccioni A, Sivalingam S, Salomoni P, Borger V, Dietrich D, Schoch S, Becker AJ (2021). Heterogeneity and excitability of BRAF V600E-induced tumors is determined by Akt/mTOR-signaling state and Trp53-loss. Neuro Oncol. Dec 1;noab268.doi: 10.1093/neuonc/noab268.
Tolve M, Ulusoy A, Patikas N, Islam K, Bodea GO, Öztürk E, Broske B, Mentani A, Wagener A, van Loo KMJ, Britsch S, Liu P, Khaled W, Metzakopian E, Baader S, Di Monte DA, Blaess S (2021). The transcription factor BCL11A defines distinct subsets of midbrain dopaminergic neurons. Cell reports. Sep 14;36(11):109697. doi: 10.1016/j.celrep.2021.109697.
Schoch S, Quatraccioni A, Robens B, Maresch R, van Loo KMJ, Kelly T, Opitz T, Borger V, Dietrich D, Pitsch J, Beck H, Becker AJ (2021). Ste20-like kinase is critical for inhibitory synapse maintenance and its deficiency confers a developmental dendritopathy. J Neurosci. Sep 29;41(39):8111-8125. doi: 10.1523/JNEUROSCI.0352-21.2021.
Pitsch J*, van Loo KMJ*, Gallus M*, Dik A*, Kamalizade D, Baumgart A, Gnatkovsky V, J. Müller A, Opitz T, Hicking G, Naik VN, Wachsmuth L, Faber C, Surges R, Kurts C, Schoch S, Melzer N, Becker AJ (2021) CD8+ T-lymphocyte driven limbic encephalitis results in temporal lobe epilepsy. Ann Neurol. 89(4):666-685. doi: 10.1002/ana.26000. (*equal contribution)
Tsortouktzidis D, Schulz H, Hamed M, Vatter H, Surges R, Schoch S, Sander T, Becker AJ, van Loo KMJ (2021) Gene expression analysis in epileptic hippocampi reveals a promoter haplotype conferring reduced aldehyde dehydrogenase 5a1 expression and responsiveness. Epilepsia. 62(1):e29-e34. doi: 10.1111/epi.16789.
Pensold D*, Reichard J*,van Loo KMJ*, Ciganok N*, Hahn A, BayerC, Liebmann L, Groß J, Tittelmeier J, Lingner T, Salinas-Riester G, Symmank J, Halfmann C, Urbach A, Gehrmann J, Costa I, Pieler T, Hübner CA, Vatter H, Kampa B, Becker AJ and Zimmer-Bensch G (2020). Synaptic function regulation through DNA methylation-mediated modulation of endocytosis in inhibitory cortical interneurons in mice. Cerebral Cortex. 2020 Jun 1;30(7):3921-3937. (*equal contribution)
van Loo KMJ and Becker AJ (2020) Transcriptional regulation of channelopathies in genetic and acquired epilepsies. Front Cell Neurosci. doi: 10.3389/fncel.2019.00587.
van Loo KMJ, Rummel CK, Pitsch J, Alexander Muller J, Bikbaev AF, Martinez Chavez E, Blaess S, Dietrich D, Heine M, Becker AJ, Schoch S (2019) Calcium channel subunit alpha2delta4 is regulated by early growth response 1 and facilitates epileptogenesis. J Neurosci. doi: 10.1523/JNEUROSCI.1731-18.2019.
Pitsch J, Kuehn JC, Gnatkovsky V, Muller JA, van Loo KMJ, de Curtis M, Vatter H, Schoch S, Elger CE, Becker AJ (2019) Anti-epileptogenic and Anti-convulsive Effects of Fingolimod in Experimental Temporal Lobe Epilepsy. Mol Neurobiol 56:1825-1840.
2005 - 2018 (Selection)
Kostoula C, Pascente R, Ravizza T, McCown T, Schoch S, Vezzani A, Becker AJ, van Loo KMJ (2018) Development of In Vivo Imaging Tools for Investigating Astrocyte Activation in Epileptogenesis. Mol Neurobiol 55:4463-4472.
Pabst M, Braganza O, Dannenberg H, Hu W, Pothmann L, Rosen J, Mody I, van Loo KM, Deisseroth K, Becker AJ, Schoch S, Beck H (2016) Astrocyte Intermediaries of Septal Cholinergic Modulation in the Hippocampus. Neuron 90:853-865.
Woitecki AM, Muller JA, van Loo KM, Sowade RF, Becker AJ, Schoch S (2016) Identification of Synaptotagmin 10 as Effector of NPAS4-Mediated Protection from Excitotoxic Neurodegeneration. J Neurosci 36:2561-2570.
van Loo KM, Schaub C, Pitsch J, Kulbida R, Opitz T, Ekstein D, Dalal A, Urbach H, Beck H, Yaari Y, Schoch S, Becker AJ (2015) Zinc regulates a key transcriptional pathway for epileptogenesis via metal-regulatory transcription factor 1. Nat Commun 6:8688.
Kulbida R, Wang Y, Mandelkow EM, Schoch S, Becker AJ, van Loo KM (2015) Molecular imaging reveals epileptogenic Ca2+-channel promoter activation in hippocampi of living mice. Brain Struct Funct 220:3067-3073.
van Loo KM, Schaub C, Pernhorst K, Yaari Y, Beck H, Schoch S, Becker AJ (2012) Transcriptional regulation of T-type calcium channel CaV3.2: bi-directionality by early growth response 1 (Egr1) and repressor element 1 (RE-1) protein-silencing transcription factor (REST). J Biol Chem 287:15489-15501.
Ekstein D, Benninger F, Daninos M, Pitsch J, van Loo KM, Becker AJ, Yaari Y (2012) Zinc induces long-term upregulation of T-type calcium current in hippocampal neurons in vivo. J Physiol 590:5895-5905.
van Loo KM, Martens GJ (2007) Genetic and environmental factors in complex neurodevelopmental disorders. Curr Genomics 8:429-444.
Coolen MW, van Loo KM, Ellenbroek BA, Cools AR, Martens GJ (2006) Ontogenic reduction of Aph-1b mRNA and gamma-secretase activity in rats with a complex neurodevelopmental phenotype. Mol Psychiatry 11:787-793.
Coolen MW, van Loo KM, van Bakel NN, Ellenbroek BA, Cools AR, Martens GJ (2006) Reduced Aph-1b expression causes tissue- and substrate-specific changes in gamma-secretase activity in rats with a complex phenotype. FASEB J 20:175-177.
Coolen MW, Van Loo KM, Van Bakel NN, Pulford DJ, Serneels L, De Strooper B, Ellenbroek BA, Cools AR, Martens GJ (2005) Gene dosage effect on gamma-secretase component Aph-1b in a rat model for neurodevelopmental disorders. Neuron 45:497-503.
