MOLECULAR BASES OF RARE BRAIN DISEASES AND CHANNELOPATHIES

Principal Investigators

Raul Estevez

Full Professor

Molecular bases of rare brain diseases and channelopathies

Research team

 

Aida Castellanos

Postdoctoral Researcher

 

Hector Gaitan

Postdoctoral Researcher

 

Marta Alonso

Early Stage Researcher

 

Laura Ferigle

Early Stage Researcher

 

Adria Pla

Early Stage Researcher

 

Efren Xicoy

Early Stage Researcher

Research Interest

 

Chloride is the most abundant anion in organisms. The plasma-membrane chloride channels of the CLC and LRRC8 family are important for various physiological functions, such as regulation of nerve- and muscle-cell excitability, both in terms of cell-volume regulation and transepithelial transport. The physiological roles of various chloride channels are illustrated in human hereditary diseases caused by mutations in the genes or auxiliary subunits which regulate their functions.

This group’s aim is therefore to try to understand chloride-channel regulation in order to provide therapeutic solutions to patients affected by this. This programme has a multidisciplinary approach, applying imaging methods, electrophysiology and biochemistry.

Technologies & Methods

 

  • Protein-protein interactions: FRET, BRET, BiFC, SplitTEV, Nanobit, coIP, Retention assays, yeast two-hybrid
  • Membrane protein solubilization and purification
  • Two electrode voltage clamp, whole-cell patch clamp, imaging methods
  • TIRF, Confocal, spinning-disk
  • Histology, zebrafish, mice studies, primary culture of glial/neurons

Featured Projects

 

    • Development of novel inhibitors of the chloride channel LRRC8/VRAC, a novel player in ischemia. Fundació La Marató de TV3. Raúl Estévez.

 

    • Estudios iniciales para determiner la estructura 3D de MLC1. CIBERER. ER20P2AC750.

 

    • Regulación de canales de cloruro en salud y enfermedad. MICINN 2019-2021. RTI2018-093493-B-I00. Raúl Estévez.

Featured Publications

 

    • Sánchez, A., García-Lareu, B., Puig, M., Prat, E., Ruberte, J., Chillón, M., Nunes, V., Estévez, R., & Bosch, A. (2020). Cerebellar Astrocyte Transduction as Gene Therapy for Megalencephalic Leukoencephalopathy. NeuroTherapeutics : Journal of the American Society for Experimental NeuroTherapeutics, 17(4), 2041–2053. https://doi.org/10.1007/s13311-020-00865-y

 

    • Elorza-Vidal, X., Xicoy-Espaulella, E., Pla-Casillanis, A., Alonso-Gardón, M., Gaitán-Peñas, H., Engel-Pizcueta, C., Fernández-Recio, J., & Estévez, R. (2020). Structural basis for the dominant or recessive character of GLIALCAM mutations found in leukodystrophies. Elorza-Vidal, X., Xicoy-Espaulella, E., Pla-Casillanis, A., Alonso-Gardón, M., Gaitán-Peñas, H., Engel-Pizcueta, C., Fernández-Recio, J., & Estévez, R. (2020). Structural basis for the dominant or recessive character of GLIALCAM mutations found in leukodystrophies. Human Molecular Genetics, 29(7), 1107–1120. https://doi.org/10.1093/hmg/ddaa009(7), 1107–1120. https://doi.org/10.1093/hmg/ddaa009

 

    • Sirisi, S., Elorza-Vidal, X., Arnedo, T., Armand-Ugón, M., Callejo, G., Capdevila-Nortes, X., López-Hernández, T., Schulte, U., Barrallo-Gimeno, A., Nunes, V., Gasull, X., & Estévez, R. (2017). Depolarization causes the formation of a ternary complex between GlialCAM, MLC1 and ClC-2 in astrocytes: implications in megalencephalic leukoencephalopathy. Human Molecular Genetics, 26(13), 2436–2450. https://doi.org/10.1093/hmg/ddx134

 

    • Hoegg-Beiler, M. B., Sirisi, S., Orozco, I. J., Ferrer, I., Hohensee, S., Auberson, M., Gödde, K., Vilches, C., de Heredia, M. L., Nunes, V., Estévez, R., & Jentsch, T. J. (2014). Disrupting MLC1 and GlialCAM and ClC-2 interactions in leukodystrophy entails glial chloride channel dysfunction. Nature Communications, 5, 3475. https://doi.org/10.1038/ncomms4475

 

    • Sirisi, S., Folgueira, M., López-Hernández, T., Minieri, L., Pérez-Rius, C., Gaitán-Peñas, H., Zang, J., Martínez, A., Capdevila-Nortes, X., De La Villa, P., Roy, U., Alia, A., Neuhauss, S., Ferroni, S., Nunes, V., Estévez, R., & Barrallo-Gimeno, A. (2014). Megalencephalic leukoencephalopathy with subcortical cysts protein 1 regulates glial surface localization of GLIALCAM from fish to humans. Human Molecular Genetics, 23(19), 5069–5086. https://doi.org/10.1093/hmg/ddu231

 

    • Capdevila-Nortes, X., López-Hernández, T., Apaja, P. M., López de Heredia, M., Sirisi, S., Callejo, G., Arnedo, T., Nunes, V., Lukacs, G. L., Gasull, X., & Estévez, R. (2013). Insights into MLC pathogenesis: GlialCAM is an MLC1 chaperone required for proper activation of volume-regulated anion currents. Human Molecular Genetics, 22(21), 4405–4416. https://doi.org/10.1093/hmg/ddt290

 

    • Jeworutzki, E., López-Hernández, T., Capdevila-Nortes, X., Sirisi, S., Bengtsson, L., Montolio, M., Zifarelli, G., Arnedo, T., Müller, C. S., Schulte, U., Nunes, V., Martínez, A., Jentsch, T. J., Gasull, X., Pusch, M., & Estévez, R. (2012). GlialCAM, a protein defective in a leukodystrophy, serves as a ClC-2 Cl(-) channel auxiliary subunit. Neuron, 73(5), 951–961. https://doi.org/10.1016/j.neuron.2011.12.039

 

    • López-Hernández, T., Ridder, M. C., Montolio, M., Capdevila-Nortes, X., Polder, E., Sirisi, S., Duarri, A., Schulte, U., Fakler, B., Nunes, V., Scheper, G. C., Martínez, A., Estévez, R., & van der Knaap, M. S. (2011). Mutant GlialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism. American Journal of Human Genetics, 88(4), 422–432. https://doi.org/10.1016/j.ajhg.2011.02.009

 

    • Duarri, A., Teijido, O., López-Hernández, T., Scheper, G. C., Barriere, H., Boor, I., Aguado, F., Zorzano, A., Palacín, M., Martínez, A., Lukacs, G. L., van der Knaap, M. S., Nunes, V., & Estévez, R. (2008). Molecular pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts: mutations in MLC1 cause folding defects. Human Molecular Genetics, 17(23), 3728–3739. https://doi.org/10.1093/hmg/ddn269

 

    • Teijido, O., Martínez, A., Pusch, M., Zorzano, A., Soriano, E., Del Río, J. A., Palacín, M., & Estévez, R. (2004). Localization and functional analyses of the MLC1 protein involved in megalencephalic leukoencephalopathy with subcortical cysts. Human Molecular Genetics, 13(21), 2581–2594. https://doi.org/10.1093/hmg/ddh291

Knowledge transfer & Innovation

 

  • Application for orphan medicinal product designation. Adeno-associated virus of serotype rh10 encoding human MLC1 under the control of GFAP promoter.