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1. A systems approach delivers a functional microRNA catalog and expanded targets for seizure suppression in temporal lobe epilepsy

Author

Venø, Morten T., Reschke, Cristina R., Morris, Gareth, Connolly, Niamh M. C., Su, Junyi, Yan, Yan, Engel, Tobias, Jimenez-Mateos, Eva M., Harder, Lea M., Pultz, Dennis, Haunsberger, Stefan J., Pal, Ajay, Heller, Janosch P., Campbell, Aoife, Langa, Elena, Brennan, Gary P., Conboy, Karen, Richardson, Amy, Norwood, Braxton A., Costard, Lara S., Neubert, Valentin, Del Gallo, Federico, Salvettik, Beatrice, Vangoor, Vamshidhar R., Sanz-Rodriguez, Amaya, Muilu, Juha, Fabene, Paolo F., Pasterkamp, R. Jeroen, Prehn, Jochen H. M., Schorge, Stephanie, Andersen, Jens S., Rosenow, Felix, Bauer, Sebastian, Kjems, Jørgen, and Henshallb, David C.

Published
2020

2. microRNA targeting of the P2X7 purinoceptor opposes a contralateral epileptogenic focus in the hippocampus

Author

Jimenez-Mateos, Eva M., Sanz-Rodriguez, Amaya, Concannon, Caoimhin, Reschke, Cristina R., Mooney, Claire M., Mooney, Catherine, Lugara, Eleonora, Morgan, James, Langa, Elena, Jimenez-Pacheco, Alba, Silva, Luiz Fernando Almeida, Mesuret, Guillaume, Boison, Detlev, Letavic, Michael, Bhattacharya, Anindya, Henshall, David C., Engel, Tobias, Díaz Hernández, Miguel, Rodríguez Artalejo, Antonio, Miras Portugal, María Teresa, Olivos Ore, Luis Alcides, Arribas Blázquez, Marina, Jimenez-Mateos, Eva M., Sanz-Rodriguez, Amaya, Concannon, Caoimhin, Reschke, Cristina R., Mooney, Claire M., Mooney, Catherine, Lugara, Eleonora, Morgan, James, Langa, Elena, Jimenez-Pacheco, Alba, Silva, Luiz Fernando Almeida, Mesuret, Guillaume, Boison, Detlev, Letavic, Michael, Bhattacharya, Anindya, Henshall, David C., Engel, Tobias, Díaz Hernández, Miguel, Rodríguez Artalejo, Antonio, Miras Portugal, María Teresa, Olivos Ore, Luis Alcides, and Arribas Blázquez, Marina

Abstract

The ATP-gated ionotropic P2X7 receptor (P2X7R) modulates glial activation, cytokine production and neurotransmitter release following brain injury. Levels of the P2X7R are increased in experimental and human epilepsy but the mechanisms controlling P2X7R expression remain poorly understood. Here we investigated P2X7R responses after focal-onset status epilepticus in mice, comparing changes in the damaged, ipsilateral hippocampus to the spared, contralateral hippocampus. P2X7Rgated inward currents were suppressed in the contralateral hippocampus and P2rx7 mRNA was selectively uploaded into the RNA-induced silencing complex (RISC), suggesting microRNA targeting. Analysis of RISC-loaded microRNAs using a high-throughput platform, as well as functional assays, suggested the P2X7R is a target of microRNA-22. Inhibition of microRNA-22 increased P2X7R expression and cytokine levels in the contralateral hippocampus after status epilepticus and resulted in more frequent spontaneous seizures in mice. The major pro-inflammatory and hyperexcitability effects of microRNA-22 silencing were prevented in P2rx7-/- mice or by treatment with a specific P2X7R antagonist. Finally, in vivo injection of microRNA-22 mimics transiently suppressed spontaneous seizures in mice. The present study supports a role for post-transcriptional regulation of the P2X7R and suggests therapeutic targeting of microRNA-22 may prevent inflammation and development of a secondary epileptogenic focus in the brain., MICINN, Comunidad de Madrid, Health Research Board, Science Foundation Ireland, Unión Europea, UCM-Banco Santander, Ion Channel Initiative, Depto. de Farmacología y Toxicología, Fac. de Veterinaria, TRUE, pub

Published
2024

3. Anti-seizure effects of JNJ-54175446 in the intra-amygdala kainic acid model of drug-resistant temporal lobe epilepsy in mice

Author

Mamad, Omar, primary, Heiland, Mona, additional, Lindner, Andreas U., additional, Hill, Thomas D. M., additional, Ronroy, Ronan M., additional, Rentrup, Kilian, additional, Sanz-Rodriguez, Amaya, additional, Langa, Elena, additional, Heller, Janosch P., additional, Moreno, Oscar, additional, Llop, Jordi, additional, Bhattacharya, Anindya, additional, Palmer, James A., additional, Ceusters, Marc, additional, Engel, Tobias, additional, and Henshall, David C., additional

Published
2024
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5. Differential microRNA editing may drive target pathway switching in human temporal lobe epilepsy

Author

Lau, Kelvin E How, primary, Nguyen, Ngoc T, additional, Kesavan, Jaideep C, additional, Langa, Elena, additional, Fanning, Kevin, additional, Brennan, Gary P, additional, Sanz-Rodriguez, Amaya, additional, Villegas-Salmerón, Javier, additional, Yan, Yan, additional, Venø, Morten T, additional, Mills, James D, additional, Rosenow, Felix, additional, Bauer, Sebastian, additional, Kjems, Jørgen, additional, and Henshall, David C, additional

Published
2023
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6. Brain cell-specific origin of circulating microRNA biomarkers in experimental temporal lobe epilepsy

Author

Brindley, Elizabeth, primary, Heiland, Mona, additional, Mooney, Catherine, additional, Diviney, Mairead, additional, Mamad, Omar, additional, Hill, Thomas D. M., additional, Yan, Yan, additional, Venø, Morten T., additional, Reschke, Cristina R., additional, Batool, Aasia, additional, Langa, Elena, additional, Sanz-Rodriguez, Amaya, additional, Heller, Janosch P., additional, Morris, Gareth, additional, Conboy, Karen, additional, Kjems, Jørgen, additional, Brennan, Gary P., additional, and Henshall, David C., additional

Published
2023
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7. MicroRNA-335-5p suppresses voltage-gated sodium channel expression and may be a target for seizure control

Author

Heiland, Mona, primary, Connolly, Niamh M. C., additional, Mamad, Omar, additional, Nguyen, Ngoc T., additional, Kesavan, Jaideep C., additional, Langa, Elena, additional, Fanning, Kevin, additional, Sanfeliu, Albert, additional, Yan, Yan, additional, Su, Junyi, additional, Venø, Morten T., additional, Costard, Lara S., additional, Neubert, Valentin, additional, Engel, Tobias, additional, Hill, Thomas D. M., additional, Freiman, Thomas M., additional, Mahesh, Arun, additional, Tiwari, Vijay K., additional, Rosenow, Felix, additional, Bauer, Sebastian, additional, Kjems, Jørgen, additional, Morris, Gareth, additional, and Henshall, David C., additional

Published
2023
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11. MicroRNA inhibition using antimiRs in acute human brain tissue sections

Author

Morris, Gareth, primary, Langa, Elena, additional, Fearon, Conor, additional, Conboy, Karen, additional, Lau E‐How, Kelvin, additional, Sanz‐Rodriguez, Amaya, additional, O'Brien, Donncha F., additional, Sweeney, Kieron, additional, Lacey, Austin, additional, Delanty, Norman, additional, Beausang, Alan, additional, Brett, Francesca M., additional, Cryan, Jane B., additional, Cunningham, Mark O., additional, and Henshall, David C., additional

Published
2022
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12. AntimiR targeting of microRNA-134 reduces seizures in a mouse model of Angelman syndrome

Author

Campbell, Aoife, primary, Morris, Gareth, additional, Sanfeliu, Albert, additional, Augusto, Joana, additional, Langa, Elena, additional, Kesavan, Jaideep C., additional, Nguyen, Ngoc T., additional, Conroy, Ronan M., additional, Worm, Jesper, additional, Kielpinski, Lukasz, additional, Jensen, Mads Aaboe, additional, Miller, Meghan T., additional, Kremer, Thomas, additional, Reschke, Cristina R., additional, and Henshall, David C., additional

Published
2022
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15. A systems approach delivers a functional microRNA catalog and expanded targets for seizure suppression in temporal lobe epilepsy

Author

TN groep Pasterkamp, Brain, Translational Neuroscience, Regenerative Medicine and Stem Cells, Venø, Morten T., Reschke, Cristina R., Morris, Gareth, Connolly, Niamh M.C., Su, Junyi, Yan, Yan, Engel, Tobias, Jimenez-Mateos, Eva M., Harder, Lea M., Pultz, Dennis, Haunsberger, Stefan J., Pal, Ajay, Heller, Janosch P., Campbell, Aoife, Langa, Elena, Brennan, Gary P., Conboy, Karen, Richardson, Amy, Norwood, Braxton A., Costard, Lara S., Neubert, Valentin, Gallo, Federico Del, Salvetti, Beatrice, Vangoor, Vamshidhar R., Sanz-Rodriguez, Amaya, Muilu, Juha, Fabene, Paolo F., Pasterkamp, R. Jeroen, Prehn, Jochen H.M., Schorge, Stephanie, Andersen, Jens S., Rosenow, Felix, Bauer, Sebastian, Kjems, Jørgen, Henshall, David C., TN groep Pasterkamp, Brain, Translational Neuroscience, Regenerative Medicine and Stem Cells, Venø, Morten T., Reschke, Cristina R., Morris, Gareth, Connolly, Niamh M.C., Su, Junyi, Yan, Yan, Engel, Tobias, Jimenez-Mateos, Eva M., Harder, Lea M., Pultz, Dennis, Haunsberger, Stefan J., Pal, Ajay, Heller, Janosch P., Campbell, Aoife, Langa, Elena, Brennan, Gary P., Conboy, Karen, Richardson, Amy, Norwood, Braxton A., Costard, Lara S., Neubert, Valentin, Gallo, Federico Del, Salvetti, Beatrice, Vangoor, Vamshidhar R., Sanz-Rodriguez, Amaya, Muilu, Juha, Fabene, Paolo F., Pasterkamp, R. Jeroen, Prehn, Jochen H.M., Schorge, Stephanie, Andersen, Jens S., Rosenow, Felix, Bauer, Sebastian, Kjems, Jørgen, and Henshall, David C.

Published
2020

16. Genetic deletion of microRNA-22 blunts the inflammatory transcriptional response to status epilepticus and exacerbates epilepsy in mice

Author

Silva, Luiz FA, primary, Reschke, Cristina R, additional, Nguyen, Ngoc T, additional, Langa, Elena, additional, Rodriguez, Amaya Sanz, additional, Gerbatin, Rogerio R, additional, Temp, Fernanda R., additional, Freitas, Mayara L., additional, Conroy, Ronan M, additional, Brennan, Gary P, additional, Engel, Tobias, additional, and Henshall, David C, additional

Published
2020
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17. Altered Biogenesis and MicroRNA Content of Hippocampal Exosomes Following Experimental Status Epilepticus

Author

Batool, Aasia, primary, Hill, Thomas D. M., additional, Nguyen, Ngoc T., additional, Langa, Elena, additional, Diviney, Mairéad, additional, Mooney, Catherine, additional, Brennan, Gary P., additional, Connolly, Niamh M. C., additional, Sanz-Rodriguez, Amaya, additional, Cavanagh, Brenton L., additional, and Henshall, David C., additional

Published
2020
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20. microRNA targeting of the P2X7 purinoceptor opposes a contralateral epileptogenic focus in the hippocampus

Author

Jimenez-Mateos, Eva M., primary, Arribas-Blazquez, Marina, additional, Sanz-Rodriguez, Amaya, additional, Concannon, Caoimhin, additional, Olivos-Ore, Luis A., additional, Reschke, Cristina R., additional, Mooney, Claire M., additional, Mooney, Catherine, additional, Lugara, Eleonora, additional, Morgan, James, additional, Langa, Elena, additional, Jimenez-Pacheco, Alba, additional, Silva, Luiz Fernando Almeida, additional, Mesuret, Guillaume, additional, Boison, Detlev, additional, Miras-Portugal, M. Teresa, additional, Letavic, Michael, additional, Artalejo, Antonio R., additional, Bhattacharya, Anindya, additional, Diaz-Hernandez, Miguel, additional, Henshall, David C., additional, and Engel, Tobias, additional

Published
2015
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21. Boronate-Tau Mediated Uptake in Neurons

Author

Pérez, Mar, primary, Cuadros, Raquel, additional, Pallas-Bazarra, Noemi, additional, García, Carlos, additional, Langa, Elena, additional, Jurado-Arjona, Jerónimo, additional, Hernández, Félix, additional, and Avila, Jesús, additional

Published
2014
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22. Patient-derived olfactory mucosa cells but not lung or skin fibroblasts mediate axonal regeneration of retinal ganglion neurons

Author

Fundación Botín, Comunidad de Madrid, Universidad Autónoma de Madrid, Ministerio de Ciencia e Innovación (España), García-Escudero, Vega, García-Gómez, Ana, Langa, Elena, Martín-Bermejo, María Jesús, Ramírez-Camacho, Rafael, García-Berrocal, José Ramón, Moreno-Flores, María Teresa, Ávila, Jesús, Fundación Botín, Comunidad de Madrid, Universidad Autónoma de Madrid, Ministerio de Ciencia e Innovación (España), García-Escudero, Vega, García-Gómez, Ana, Langa, Elena, Martín-Bermejo, María Jesús, Ramírez-Camacho, Rafael, García-Berrocal, José Ramón, Moreno-Flores, María Teresa, and Ávila, Jesús

Abstract

Although human olfactory mucosa derived cells (OMC) have been used in animal models and clinical trials with CNS repair purposes, the exact identity of these cells in culture with respect to their tissue of origin is not fully understood and their neuroregenerative capacity in vitro has not yet been demonstrated. In this study we have compared human OMC with human ensheathing glia from olfactory bulb (OB) and human fibroblasts from skin and lung. Our results indicate that these different cultured cell types exhibit considerable overlap of antigenic markers such that it is presently not possible to distinguish them immunocytochemically. However, in rat retinal ganglion neuron coculture assays the axonal regenerative activity of OMC and OB ensheathing glia was dramatically higher than that exhibited by all fibroblast samples, confirming neuroregenerative activity as a unique property shared by cultured cells derived from the human olfactory system. © 2011 Elsevier Ireland Ltd.

Published
2012

24. Prevention of Senescence Progression in Reversibly Immortalized Human Ensheathing Glia Permits Their Survival After Deimmortalization

Author

García-Escudero, Vega, primary, García-Gómez, Ana, additional, Gargini, Ricardo, additional, Martín-Bermejo, María J, additional, Langa, Elena, additional, de Yébenes, Justo G, additional, Delicado, Alicia, additional, Ávila, Jesús, additional, Moreno-Flores, María T, additional, and Lim, Filip, additional

Published
2010
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25. AntimiR targeting of microRNA-134 reduces seizures in a mouse model of Angelman syndrome.

Author

Campbell A, Morris G, Sanfeliu A, Augusto J, Langa E, Kesavan JC, Nguyen NT, Conroy RM, Worm J, Kielpinski L, Jensen MA, Miller MT, Kremer T, Reschke CR, and Henshall DC

Abstract

Angelman syndrome (AS) is a severe neurodevelopmental disorder featuring ataxia, cognitive impairment, and drug-resistant epilepsy. AS is caused by mutations or deletion of the maternal copy of the paternally imprinted UBE3A gene, with current precision therapy approaches focusing on re-expression of UBE3A . Certain phenotypes, however, are difficult to rescue beyond early development. Notably, a cluster of microRNA binding sites was reported in the untranslated Ube3a1 transcript, including for miR-134, suggesting that AS may be associated with microRNA dysregulation. Here, we report levels of miR-134 and key targets are normal in the hippocampus of mice carrying a maternal deletion of Ube3a ( Ube3a m-/p+ ). Nevertheless, intracerebroventricular injection of an antimiR oligonucleotide inhibitor of miR-134 (Ant-134) reduced audiogenic seizure severity over multiple trials in 21- and 42-day-old AS mice. Interestingly, Ant-134 also improved distance traveled and center crossings of AS mice in the open-field test. Finally, we show that silencing miR-134 can upregulate targets of miR-134 in neurons differentiated from Angelman patient-derived induced pluripotent stem cells. These findings indicate that silencing miR-134 and possibly other microRNAs could be useful to treat clinically relevant phenotypes with a later developmental window in AS., Competing Interests: The Royal College of Surgeons in Ireland (D.C.H.) holds a patent for the inhibition of microRNA-134 for the treatment of seizure-related disorders and other neurologic injuries (US 9,803,200 B2). J.W., M.A.J., and M.T.M. are employees of F Hoffman-La Roche Ltd. All other authors have no competing interests., (© 2022 The Author(s).)

Published
2022
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26. De-repression of myelin-regulating gene expression after status epilepticus in mice lacking the C/EBP homologous protein CHOP.

Author

Sheedy C, Mooney C, Jimenez-Mateos E, Sanz-Rodriguez A, Langa E, Mooney C, and Engel T

Abstract

The C/EBP homologous protein CHOP is normally present at low levels in cells but increases rapidly after insults such as DNA damage or endoplasmatic reticulum stress where it contributes to cellular homeostasis and apoptosis. By forming heterodimers with other transcription factors, CHOP can either act as a dominant-negative regulator of gene expression or to induce the expression of target genes. Recent work demonstrated that seizure-induced hippocampal damage is significantly worse in mice lacking CHOP and these animals go on to develop an aggravated epileptic phenotype. To identify novel CHOP-controlled target genes which potentially influence the epileptic phenotype, we performed a bioinformatics analysis of tissue microarrays from chop-deficient mice after prolonged seizures. GO analysis revealed genes associated with biological membranes were prominent among those in the chop-deficient array dataset and we identified myelin-associated genes to be particularly de-repressed. These data suggest CHOP might act as an inhibitor of myelin-associated processes in the brain and could be targeted to influence axonal regeneration or reorganisation.

Published
2014

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