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2. Astroglial toxicity promotes synaptic degeneration in the thalamocortical circuit in frontotemporal dementia with GRN mutations

Author

Elise Marsan, Dmitry Velmeshev, Arren Ramsey, Ravi K. Patel, Jiasheng Zhang, Mark Koontz, Madeline G. Andrews, Martina de Majo, Cristina Mora, Jessica Blumenfeld, Alissa N. Li, Salvatore Spina, Lea T. Grinberg, William W. Seeley, Bruce L. Miller, Erik M. Ullian, Matthew F. Krummel, Arnold R. Kriegstein, and Eric J. Huang

Subjects
Neuroscience, Medicine
Abstract

Mutations in the human progranulin (GRN) gene are a leading cause of frontotemporal lobar degeneration (FTLD). While previous studies implicate aberrant microglial activation as a disease-driving factor in neurodegeneration in the thalamocortical circuit in Grn–/– mice, the exact mechanism for neurodegeneration in FTLD-GRN remains unclear. By performing comparative single-cell transcriptomics in the thalamus and frontal cortex of Grn–/– mice and patients with FTLD-GRN, we have uncovered a highly conserved astroglial pathology characterized by upregulation of gap junction protein GJA1, water channel AQP4, and lipid-binding protein APOE, and downregulation of glutamate transporter SLC1A2 that promoted profound synaptic degeneration across the two species. This astroglial toxicity could be recapitulated in mouse astrocyte-neuron cocultures and by transplanting induced pluripotent stem cell–derived astrocytes to cortical organoids, where progranulin-deficient astrocytes promoted synaptic degeneration, neuronal stress, and TDP-43 proteinopathy. Together, these results reveal a previously unappreciated astroglial pathology as a potential key mechanism in neurodegeneration in FTLD-GRN.

Published
2023
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3. Depdc5 knockout rat: A novel model of mTORopathy

Author

Elise Marsan, Saeko Ishida, Adrien Schramm, Sarah Weckhuysen, Giuseppe Muraca, Sarah Lecas, Ning Liang, Caroline Treins, Mario Pende, Delphine Roussel, Michel Le Van Quyen, Tomoji Mashimo, Takehito Kaneko, Takashi Yamamoto, Tetsushi Sakuma, Séverine Mahon, Richard Miles, Eric Leguern, Stéphane Charpier, and Stéphanie Baulac

Subjects
DEPDC5, Familial focal epilepsy, Focal cortical dysplasia, mTOR, Rapamycin, Knockout, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

DEP-domain containing 5 (DEPDC5), encoding a repressor of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, has recently emerged as a major gene mutated in familial focal epilepsies and focal cortical dysplasia. Here we established a global knockout rat using TALEN technology to investigate in vivo the impact of Depdc5-deficiency. Homozygous Depdc5−/− embryos died from embryonic day 14.5 due to a global growth delay. Constitutive mTORC1 hyperactivation was evidenced in the brains and in cultured fibroblasts of Depdc5−/− embryos, as reflected by enhanced phosphorylation of its downstream effectors S6K1 and rpS6. Consistently, prenatal treatment with mTORC1 inhibitor rapamycin rescued the phenotype of Depdc5−/− embryos. Heterozygous Depdc5+/− rats developed normally and exhibited no spontaneous electroclinical seizures, but had altered cortical neuron excitability and firing patterns. Depdc5+/− rats displayed cortical cytomegalic dysmorphic neurons and balloon-like cells strongly expressing phosphorylated rpS6, indicative of mTORC1 upregulation, and not observed after prenatal rapamycin treatment. These neuropathological abnormalities are reminiscent of the hallmark brain pathology of human focal cortical dysplasia. Altogether, Depdc5 knockout rats exhibit multiple features of rodent models of mTORopathies, and thus, stand as a relevant model to study their underlying pathogenic mechanisms.

Published
2016
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5. Endosomal recycling defects link Huntington's disease with McLeod syndrome

Author

Eric Huang and Elise Marsan

Subjects
Manganese, Amino Acid Transport Systems, Neutral, Huntington Disease, rab GTP-Binding Proteins, Cell Membrane, Humans, Cell Biology, Endosomes, Neuroacanthocytosis
Abstract

Chhetri and colleagues (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202112073) show that Rab11-mediated endosomal recycling regulates cell surface expression of McLeod syndrome protein XK. Mutant huntingtin interferes with the recycling of XK to the cell surface and significantly reduces manganese transport across cell membrane.

Published
2023

6. Review: Mechanistic target of rapamycin (mTOR) pathway, focal cortical dysplasia and epilepsy

Author

Elise Marsan, Stéphanie Baulac, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Gestionnaire, Hal Sorbonne Université, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
focal epilepsy, 0301 basic medicine, Hemimegalencephaly, DEPDC5, Histology, Somatic cell, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, GATOR1, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), medicine, Humans, Mechanistic target of rapamycin, PI3K/AKT/mTOR pathway, Epilepsy, biology, Cell growth, TOR Serine-Threonine Kinases, Autophagy, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cortical dysplasia, medicine.disease, 3. Good health, mTOR pathway, 030104 developmental biology, Neurology, Malformations of Cortical Development, Group I, biology.protein, Cancer research, somatic mutations, Neurology (clinical), focal cortical dysplasia, 030217 neurology & neurosurgery, Signal Transduction
Abstract

International audience; Over the last decade, there has been increasing evidence that hyperactivation of the mechanistic target of rapamycin (mTOR) pathway is a hallmark of malformations of cortical development such as focal cortical dysplasia (FCD) or hemimegalencephaly. The mTOR pathway governs protein and lipid synthesis, cell growth and proliferation as well as metabolism and autophagy. The molecular genetic aetiology of mTOR hyperactivation has only been recently clarified. This article will review the current and still evolving genetic advances in the elucidation of the molecular basis of FCD. Activating somatic mutations in the MTOR gene are to date the most frequent mutations found in FCD brain specimens.

Published
2018
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7. Depdc5 knockdown causes mTOR-dependent motor hyperactivity in zebrafish

Author

Hortense de Calbiac, Adriana Dabacan, Elise Marsan, Hervé Tostivint, Gabrielle Devienne, Saeko Ishida, Eric Leguern, Stéphanie Baulac, Raul C. Muresan, Edor Kabashi, Sorana Ciura, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Evolution des régulations endocriniennes (ERE), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2018
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8. Familial focal epilepsy with focal cortical dysplasia due toDEPDC5mutations

Author

Mailys Daniau, Fabienne Picard, Doug Nordli, Franck Bielle, Eric LeGuern, Arnaud Biraben, Frederick Andermann, Dang Khoa Nguyen, Virginie Lambrecq, Eva Andermann, Francine Chassoux, Stéphanie Baulac, Saeko Ishida, Elise Marsan, Catherine Miquel, Sylvie Nguyen, Mihaela Vlaicu, and Patrick Cossette

Subjects
Pathology, medicine.medical_specialty, Mutation, medicine.diagnostic_test, Brain biopsy, Biology, Cortical dysplasia, Bioinformatics, medicine.disease, medicine.disease_cause, DEPDC5, Germline, 3. Good health, Epilepsy, Germline mutation, Neurology, medicine, Epilepsy surgery, Neurology (clinical)
Abstract

Objective The DEPDC5 (DEP domain-containing protein 5) gene, encoding a repressor of the mTORC1 signaling pathway, has recently emerged as a major gene mutated in familial focal epilepsies. We aimed to further extend the role of DEPDC5 to focal cortical dysplasias (FCDs). Methods Seven patients from 4 families with DEPDC5 mutations and focal epilepsy associated with FCD were recruited and investigated at the clinical, neuroimaging, and histopathological levels. The DEPDC5 gene was sequenced from genomic blood and brain DNA. Results All patients had drug-resistant focal epilepsy, 5 of them underwent surgery, and 1 had a brain biopsy. Electroclinical phenotypes were compatible with FCD II, although magnetic resonance imaging (MRI) was typical in only 4 cases. Histopathology confirmed FCD IIa in 2 patients (including 1 MRI-negative case) and showed FCD I in 2 other patients, and remained inconclusive in the last 2 patients. Three patients were seizure-free postsurgically, and 1 had a worthwhile improvement. Sequencing of blood DNA revealed truncating DEPDC5 mutations in all 4 families; 1 mutation was found to be mosaic in an asymptomatic father. A brain somatic DEPDC5 mutation was identified in 1 patient in addition to the germline mutation. Interpretation Germline, germline mosaic, and brain somatic DEPDC5 mutations may cause epilepsy associated with FCD, reinforcing the link between mTORC1 pathway and FCDs. Similarly to other mTORopathies, a “2-hit” mutational model could be responsible for cortical lesions. Our study also indicates that epilepsy surgery is a valuable alternative in the treatment of drug-resistant DEPDC5-positive focal epilepsies, even if the MRI is unremarkable.

Published
2015
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9. Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy

Author

Giuseppe Muraca, Sara Baldassari, Delphine Roussel, Richard B. Miles, Alexandre Bacq, Vincent Navarro, Eric LeGuern, Elise Marsan, Théo Ribierre, Stéphanie Baulac, Charlotte Deleuze, and Mathilde Chipaux

Subjects
0301 basic medicine, Male, Somatic cell, Repressor, Biology, Mechanistic Target of Rapamycin Complex 1, medicine.disease_cause, Germline, 03 medical and health sciences, Epilepsy, Mice, 0302 clinical medicine, medicine, Animals, Humans, Germ-Line Mutation, Neurons, Mutation, Concise Communication, GTPase-Activating Proteins, General Medicine, Dendrites, Cortical dysplasia, medicine.disease, DEPDC5, Mice, Mutant Strains, Spine, Malformations of Cortical Development, Repressor Proteins, 030104 developmental biology, Dysplasia, Commentary, Female, Epilepsies, Partial, CRISPR-Cas Systems, Neuroscience, 030217 neurology & neurosurgery
Abstract

DEP domain-containing 5 protein (DEPDC5) is a repressor of the recently recognized amino acid-sensing branch of the mTORC1 pathway. So far, its function in the brain remains largely unknown. Germline loss-of-function mutations in DEPDC5 have emerged as a major cause of familial refractory focal epilepsies, with case reports of sudden unexpected death in epilepsy (SUDEP). Remarkably, a fraction of patients also develop focal cortical dysplasia (FCD), a neurodevelopmental cortical malformation. We therefore hypothesized that a somatic second-hit mutation arising during brain development may support the focal nature of the dysplasia. Here, using postoperative human tissue, we provide the proof of concept that a biallelic 2-hit - brain somatic and germline - mutational mechanism in DEPDC5 causes focal epilepsy with FCD. We discovered a mutation gradient with a higher rate of mosaicism in the seizure-onset zone than in the surrounding epileptogenic zone. Furthermore, we demonstrate the causality of a Depdc5 brain mosaic inactivation using CRISPR-Cas9 editing and in utero electroporation in a mouse model recapitulating focal epilepsy with FCD and SUDEP-like events. We further unveil a key role of Depdc5 in shaping dendrite and spine morphology of excitatory neurons. This study reveals promising therapeutic avenues for treating drug-resistant focal epilepsies with mTORC1-targeting molecules.

Published
2017

10. Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia

Author

Sarah Weckhuysen, Margitta Seeck, Bart Dermaut, Alfred Meurs, Michel Baulac, Stéphanie Baulac, Pierre de la Grange, Francine Chassoux, Elise Marsan, Fabienne Picard, Eric LeGuern, Cécile Marchal, Pierre Thomas, Isabelle An-Gourfinkel, Mélanie Morin-Brureau, Christine Kallay Zetchi, Virginie Lambrecq, Martine Fohlen, HAL-UPMC, Gestionnaire, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des épilepsies rares [CHU Pitié-Salpêtrière], Unité fonctionnelle d'épilepsie [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Service de Neurologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'épileptologie [CHU de Bordeaux], CHU Bordeaux [Bordeaux], Service de Neurochirurgie Pediatrique, Fondation Ophtalmologique Rotschild, Department of Neurology [Genève], Hôpitaux Universitaires de Genève (HUG), University of Geneva Medical School, Center for Medical Genetics [Ghent], Ghent University Hospital, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Dpt of Neurology [Gent], Service de Neurologie [CHU Nice], Hôpital Pasteur [Nice] (CHU)-Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Hospitalier Sainte Anne, Centre hospitalier Sainte Anne, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Service de Neurologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Neuroprotection & Neuromodulation

Subjects
0301 basic medicine, Male, DEPDC5, DNA Mutational Analysis, mTORC1, Gene mutation, Cohort Studies, Epilepsy, 0302 clinical medicine, genetics, Child, Medicine(all), Aged, 80 and over, TOR Serine-Threonine Kinases, GTPase-Activating Proteins, Middle Aged, NPRL3, Magnetic Resonance Imaging, 3. Good health, Malformations of Cortical Development, mTOR pathway, Neurology, SUDEP 22 text pages, Child, Preschool, 5 figures, 1 table, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Adult, Biology, 03 medical and health sciences, Young Adult, familial focal epilepsies, NPRL2, medicine, Humans, Genetic Predisposition to Disease, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], PI3K/AKT/mTOR pathway, 35 references, Aged, Family Health, Tumor Suppressor Proteins, Infant, Newborn, fical cortical dysplasia, Infant, GATOR2 complex, Cortical dysplasia, 3249 words (including summary), medicine.disease, complex genes, ddc:616.8, Repressor Proteins, 030104 developmental biology, Positron-Emission Tomography, Involvement of Gator, Mutation, Cancer research, Neurology (clinical), Epilepsies, Partial, Human medicine, Neuroscience, 030217 neurology & neurosurgery
Abstract

International audience; ObjectiveThe discovery of mutations in DEPDC5 in familial focal epilepsies has introduced a novel pathomechanism to a field so far dominated by ion channelopathies. DEPDC5 is part of a complex named GAP activity toward RAGs (GATOR) complex 1 (GATOR1), together with the proteins NPRL2 and NPRL3, and acts to inhibit the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) pathway. GATOR1 is in turn inhibited by the GATOR2 complex. The mTORC1 pathway is a major signaling cascade regulating cell growth, proliferation, and migration. We aimed to study the contribution of GATOR complex genes to the etiology of focal epilepsies and to describe the associated phenotypical spectrum.MethodsWe performed targeted sequencing of the genes encoding the components of the GATOR1 (DEPDC5, NPRL2, and NPRL3) and GATOR2 (MIOS, SEC13, SEH1L, WDR24, and WDR59) complex in 93 European probands with focal epilepsy with or without focal cortical dysplasia. Phospho-S6 immunoreactivity was used as evidence of mTORC1 pathway activation in resected brain tissue of patients carrying pathogenic variants.ResultsWe identified four pathogenic variants in DEPDC5, two in NPRL2, and one in NPRL3. We showed hyperactivation of the mTORC1 pathway in brain tissue from patients with NPRL2 and NPRL3 mutations. Collectively, inactivating mutations in GATOR1 complex genes explained 11% of cases of focal epilepsy, whereas no pathogenic mutations were found in GATOR2 complex genes. GATOR1-related focal epilepsies differ clinically from focal epilepsies due to mutations in ion channel genes by their association with focal cortical dysplasia and seizures emerging from variable foci, and might confer an increased risk of sudden unexplained death in epilepsy (SUDEP).SignificanceGATOR1 complex gene mutations leading to mTORC1 pathway upregulation is an important cause of focal epilepsy with cortical malformations and represents a potential target for novel therapeutic approaches.

Published
2016
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11. Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy

Author

Susan M. Hiatt, Sarah Weckhuysen, E. Martina Bebin, Stéphanie Baulac, Virginie Lambrecq, Sarah Ferrand-Sorbets, Line H.G. Larsen, Valerio Conti, Georg Dorfmüller, Jeremy W. Prokop, Elise Marsan, Rikke S. Møller, Gregory M. Cooper, Kevin M. Bowling, Eric LeGuern, Davide Mei, Pierre de la Grange, Mathilde Chipaux, Valérie Taly, Renzo Guerrini, Guido Rubboli, The Danish Epilepsy Centre Filadelfia [Dianalund, Denmark], Institute for Regional Health Services [Odense, Denmark], University of Southern Denmark (SDU), Centre de référence des épilepsies rares [CHU Pitié-Salpêtrière], Unité fonctionnelle d'épilepsie [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Service de Neurologie [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie pédiatrique [Fondation Rothschild, Paris], Fondation Rothschild, Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), HudsonAlpha Institute for Biotechnology [Huntsville, AL], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pediatric Neurology & Neurogenetics Unit and Laboratories, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)-Children's Hospital A. Meyer, TALY, Valerie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Service de Neurologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Università degli Studi di Firenze = University of Florence (UniFI)-Children's Hospital A. Meyer

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Autosomal dominant nocturnal frontal lobe epilepsy, Germline, Article, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Germline mutation, medicine, Journal Article, Missense mutation, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Genetics (clinical), Genetics, business.industry, Pharmacology. Therapy, Macrocephaly, Cortical dysplasia, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Epilepsy syndromes, Cancer research, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Human medicine, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

OBJECTIVE: To assess the prevalence of somatic MTOR mutations in focal cortical dysplasia (FCD) and of germline MTOR mutations in a broad range of epilepsies.METHODS: We collected 20 blood-brain paired samples from patients with FCD and searched for somatic variants using deep-targeted gene panel sequencing. Germline mutations in MTOR were assessed in a French research cohort of 93 probands with focal epilepsies and in a diagnostic Danish cohort of 245 patients with a broad range of epilepsies. Data sharing among collaborators allowed us to ascertain additional germline variants in MTOR.RESULTS: We detected recurrent somatic variants (p.Ser2215Phe, p.Ser2215Tyr, and p.Leu1460Pro) in the MTOR gene in 37% of participants with FCD II and showed histologic evidence for activation of the mTORC1 signaling cascade in brain tissue. We further identified 5 novel de novo germline missense MTOR variants in 6 individuals with a variable phenotype from focal, and less frequently generalized, epilepsies without brain malformations, to macrocephaly, with or without moderate intellectual disability. In addition, an inherited variant was found in a mother-daughter pair with nonlesional autosomal dominant nocturnal frontal lobe epilepsy.CONCLUSIONS: Our data illustrate the increasingly important role of somatic mutations of the MTOR gene in FCD and germline mutations in the pathogenesis of focal epilepsy syndromes with and without brain malformation or macrocephaly.

Published
2016
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12. Glutamatergic neuron-targeted loss of LGI1 epilepsy gene results in seizures

Author

Jérôme Garrigue, Eric LeGuern, Morgane Boillot, Benoit Martin, Richard B. Miles, Vincent Navarro, Elise Marsan, Matthew P. Anderson, Béatrice Dufresnois, Katia Lehongre, Ekim Ozkaynak, Stéphanie Baulac, Saeko Ishida, Clément Huneau, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de neurosciences cognitives et d'imagerie cérébrale (LENA), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Biology, Inhibitory postsynaptic potential, 03 medical and health sciences, Glutamatergic, Epilepsy, Mice, 0302 clinical medicine, Interneurons, Seizures, Conditional gene knockout, medicine, Animals, GABAergic Neurons, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Mice, Knockout, Neurons, 0303 health sciences, Pyramidal Cells, Limbic encephalitis, Age Factors, Intracellular Signaling Peptides and Proteins, Brain, Proteins, Electroencephalography, Original Articles, medicine.disease, Embryo, Mammalian, medicine.anatomical_structure, nervous system, Animals, Newborn, Convulsant, biology.protein, Neurology (clinical), Neuron, Neuroscience, 030217 neurology & neurosurgery, Parvalbumin, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Leucin-rich, glioma inactivated 1 (LGI1) is a secreted protein linked to human seizures of both genetic and autoimmune aetiology. Mutations in the LGI1 gene are responsible for autosomal dominant temporal lobe epilepsy with auditory features, whereas LGI1 autoantibodies are involved in limbic encephalitis, an acquired epileptic disorder associated with cognitive impairment. We and others previously reported that Lgi1-deficient mice have early-onset spontaneous seizures leading to premature death at 2-3 weeks of age. Yet, where and when Lgi1 deficiency causes epilepsy remains unknown. To address these questions, we generated Lgi1 conditional knockout (cKO) mice using a set of universal Cre-driver mouse lines. Selective deletion of Lgi1 was achieved in glutamatergic pyramidal neurons during embryonic (Emx1-Lgi1cKO) or late postnatal (CaMKIIα-Lgi1cKO) developmental stages, or in gamma amino butyric acidergic (GABAergic) parvalbumin interneurons (PV-Lgi1cKO). Emx1-Lgi1cKO mice displayed early-onset and lethal seizures, whereas CaMKIIα-Lgi1cKO mice presented late-onset occasional seizures associated with variable reduced lifespan. In contrast, neither spontaneous seizures nor increased seizure susceptibility to convulsant were observed when Lgi1 was deleted in parvalbumin interneurons. Together, these data showed that LGI1 depletion restricted to pyramidal cells is sufficient to generate seizures, whereas seizure thresholds were unchanged after depletion in gamma amino butyric acidergic parvalbumin interneurons. We suggest that LGI1 secreted from excitatory neurons, but not parvalbumin inhibitory neurons, makes a major contribution to the pathogenesis of LGI1-related epilepsies. Our data further indicate that LGI1 is required from embryogenesis to adulthood to achieve proper circuit functioning.

Published
2014
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13. Depdc5 knockout rat: A novel model of mTORopathy

Author

Caroline Treins, Delphine Roussel, Takashi Yamamoto, Michel Le Van Quyen, Mario Pende, Richard B. Miles, Stéphanie Baulac, Saeko Ishida, Tomoji Mashimo, Séverine Mahon, Takehito Kaneko, Ning Liang, Elise Marsan, Sarah Lecas, Tetsushi Sakuma, Stéphane Charpier, Adrien E. Schramm, Eric LeGuern, Sarah Weckhuysen, Giuseppe Muraca, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute of Experimental Animal Sciences, Osaka University, Institute of Laboratory Animals, Kyoto University, Department of Mathematical and Life Sciences, Hiroshima University, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), HAL-UPMC, Gestionnaire, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -CHU Pitié-Salpêtrière [APHP], Institut Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP]

Subjects
0301 basic medicine, Pathology, Knockout rat, DEPDC5, mTORC1, Animals, Genetically Modified, Gene Knockout Techniques, 0302 clinical medicine, Phosphorylation, Cerebral Cortex, Neurons, TOR Serine-Threonine Kinases, 3. Good health, Cell biology, Neurology, mTOR, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Signal Transduction, medicine.medical_specialty, Genotype, Knockout, Embryonic Development, P70-S6 Kinase 1, Mechanistic Target of Rapamycin Complex 1, Biology, Focal cortical dysplasia, lcsh:RC321-571, 03 medical and health sciences, Downregulation and upregulation, medicine, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Rapamycin, Rats, Wistar, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Sirolimus, Fibroblasts, Cortical dysplasia, medicine.disease, Familial focal epilepsy, Embryonic stem cell, Rats, Inbred F344, Rats, Repressor Proteins, Disease Models, Animal, 030104 developmental biology, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Multiprotein Complexes, 030217 neurology & neurosurgery
Abstract

International audience; DEP-domain containing 5 (DEPDC5), encoding a repressor of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, has recently emerged as a major gene mutated in familial focal epilepsies and focal cortical dysplasia. Here we established a global knockout rat using TALEN technology to investigate in vivo the impact of Depdc5-deficiency. Homozygous Depdc5−/− embryos died from embryonic day 14.5 due to a global growth delay. Constitutive mTORC1 hyperactivation was evidenced in the brains and in cultured fibroblasts of Depdc5−/− embryos, as reflected by enhanced phosphorylation of its downstream effectors S6K1 and rpS6. Consistently, prenatal treatment with mTORC1 inhibitor rapamycin rescued the phenotype of Depdc5−/− embryos. Heterozygous Depdc5+/− rats developed normally and exhibited no spontaneous electroclinical seizures, but had altered cortical neuron excitability and firing patterns. Depdc5+/− rats displayed cortical cytomegalic dysmorphic neurons and balloon-like cells strongly expressing phosphorylated rpS6, indicative of mTORC1 upregulation, and not observed after prenatal rapamycin treatment. These neuropathological abnormalities are reminiscent of the hallmark brain pathology of human focal cortical dysplasia. Altogether, Depdc5 knockout rats exhibit multiple features of rodent models of mTORopathies, and thus, stand as a relevant model to study their underlying pathogenic mechanisms.

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