Research Interests and Main Results

The main focus of the ‘EPIPATH’ group (EPIlepsies and comorbid PATHologies) is on the study and on the understanding of the relationships between the epilepsies on the one hand, and the numerous other brain disorders the epilepsies may be associated with on the other hand: autistic manifestations, cognitive impairment, speech and language impairments, paroxysmal dyskinesia, migraines, etc. Generally the project should be viewed in the context of the relationships linking brain pathologies and the development of the brain, and aims at deciphering the pathophysiology of the epilepsies and of their comorbid conditions. The approach is multidisciplinary and includes the clinical, genetic, molecular, biochemical, cellular, electrophysiological, and therapeutic levels.

In the last years, the key steps of our research activity can be summarized as follows:

Infantile Seizures, Paroxysmal Dyskinesia, and Migraines

Long after our initial reports on the existence of a shared genetic basis for infantile seizures and paroxysmal dyskinesia, via the mapping of the genetic locus (Szepetowski et al. 1997; Lee et al. 1998), we have recently identified the disease gene, PRRT2 (Lee et al. 2012), in the context of an international consortium. PRRT2 (Proline-Rich Transmembrane Protein 2) encodes a protein possibly involved in exocytosis and in neurotransmitter release. This represents a major step towards the understanding of the underlying mechanisms sustaining those comorbid associations. We then rapidly expanded the phenotypic spectrum of PRRT2 mutations to migraines, notably hemiplegic (Cloarec et al. 2012).

Drug-Resistant Mesial Temporal Lobe Epilepsies

We have shown an alteration of the complement system (C3) in the epileptogenic zones of patients with mesial temporal lobe epilepsies (Jamali et al. 2006). Those results fit well with the increasing evidences for a crucial role of the complement system in the functioning, the development and the pathology of the central nervous system. Since then we have shown that the C3 gene participates in the genetic susceptibility to febrile seizures and to drug-resistant epilepsies (Jamali et al. 2010).

Epilepsy, Language and Developpement (the epilepsy-aphasia spectrum)

Following the identification of two mutations in the SRPX2 (Sushi-Repat Protein, X-linked 2) gene (Roll et al. 2006) in focal (Rolandic) epilepsies with language impairment or with polymicrogyria, we have characterized SRPX2-related pathophysiological pathways: we identified a SRPX2 receptor, uPAR (plasminogen activator receptor of the urokinase type) (Royer-Zemmour et al. 2008), which is indeed implicated in the develoment of the brain and in the migration/maturation of interneurons; we have then shown that both the SRPX2 and uPAR genes are regulated by the transcription factor FOXP2 (Roll et al. 2010), which in turn is mutated in language disorders (verbal dyspraxia). The direct role of the SRPX2 mutations is currently being challenged; indeed, SRPX2 might well be considered as a genetic susceptibility factor to various neurodevelopemental disorders. Nevertheless the crucial role of Srpx2 in the development of the rat cerebral cortex, in radial neuronal migration, and in the acetylation of alpha-tubulins (Salmi et al. 2013), confirms the strong cerebral impact of Srpx2 defects. The crucial role of Srpx2 in the developing cerebral cortex has been recently emphasized independently in the mouse, by showing that Srpx2 is involved in synaptogenesis and in ultrasound vocalization. Overall our data on SRPX2 fit well with the general view on the links between the migration of projection neurons, tubulin acetylation, and developmental alterations of the cerebral cortex. In this context, we have also shown that a single maternal injection of tubacin (an inhibitor of HDAC6 tubulin deacetylase) during pregnancy, robustly prevents against neuronal migration defects in the embryos and against the long-term postnatal epileptiform manifestations caused by in utero Srpx2 invalidation (Salmi et al. 2013). This conceptually important data represents a proof-of-concept for the pharmacological prevention of early alterations in the developing brain, and of their long-term postnatal consequences.

In parallel with those findings, we have identified mutations in the GRIN2A gene that represent a first and major cause for focal epilepsies and epileptic encephalopathies with speech and language disorders (epilepsy-aphasia spectrum : Rolandic epilepsy, Landau-Kleffner syndrome, continuous spike and wave during slow-wave sleep syndrome). Numerous mutations of various types (microdeletions, nonsense, splice-site,missense) in GRIN2A, which encodes the GluN2A subunit of NMDA glutamate receptors, were found in about 20% of cases (Lesca et al. 2013; Carvill et al. 2013). Several articles published since then have confirmed our two former publications. The mutations lead to functional consequences of various types, which is consistent with the likely complexity of the underlying mechanisms. Overall our data represent a major and crucial step in this field. We may now consider the possibility of a better understanding, at various levels, of the underlying pathophysiology, and the design of novel therapeutic strategies in the appropriate animal models.

Current research projects

Three main projects are currently being performed:

[A] Pathophysiology of focal epilepsies and of epileptic encephalopathies of the epilepsy-aphasia spectrum: exploration of Srpx2 and of Grin2a invalidation murine models.
[B] Genetics and pathophysiology of absence epilepsy with photosensitivity and eyelid myoclonia.
[C] Pathophysiology of congenital cytomegalovirus infections of the brain: analysis of a rat model of in utero infection of the brain.

Key words

Epilepsy / Language /Brain development / Genetics / SRPX2 / GRIN2A / Cytomegalovirus / Therapeutic models

Experimental approaches

Genetic and genomic screenings (external collaboration), Animal (rodent) models (rat, mouse), RNA interference in utero,  immunohistochemistry, confocal microscopy, video-microscopy (external collaboration), cell and molecular biology, flow cytometry (external collaboration), biochemistry, small animal imaging (external collaboration), behavioral analyzes, electrophysiology (internal collaboration).

Recent and/or Ongoing Collaborations

Internal (INMED)
- PPGI platform : E Buhler
- InMagic platform : F Michel
-PBMC platform : E Pallesi
-  ‘Cortical development disorders and neuronal migration’ Group : C Cardoso, A Represa
-  ‘Epilepsies and childhood diseases’ Group : N Burnashev
- Neurochlore : Y Ben Ari

Local (Marseille)
- IBDML, CNRS UMR7288 : P Durbec
- Mass spectrometry Platform PIT2, CRO2, INSERM U911 : C Villard, D Laffite
- Immunophenomics Centre (CIPHE), CIML : P Grenot, H Luche, M Malissen

National
- Neuroscience Centre, CNRS UMR5292 et INSERM U1028, Lyon : L Bezin, P Ryvlin
- Department of Molecular Cytogenetics, Lyon : G Lesca, D Sanlaville
- Paediatric Neurology, Lyon : A Arzimanoglou
- Department of Neurology, Strasbourg : E Hirsch, G Rudolf
- INSERM U925, Amiens : J Rochette
- CERMEP, Lyon : R Bolbos, JB Langlois
- Inserm U1141, Paris : H Adle-Biassette, N Tessier, P Gressens

International (In Europe)
- Wellcome Trust Centre, Oxford University (UK) & Max Planck Institute for Psycholinguistics, Nijmegen (The Netherlands) : SE Fisher
- Nuffield Clinical Department of Neurosciences, University of Oxford (UK) : A Vincent
- Department of Pathology & Immunology, Geneva University (Switzerland) : BA Imhof
- Department of Clinical Neurosciences, King’s college London (UK) : D Pal
- Department of Clinical and Molecular Virology, University of Erlangen-Nuremberg (Germany) : T Stamminger

International (Outside Europe)
- Vaccine and Gene Therapy Institute, Oregon University, Portland (USA) : DN Streblow
- Division of Genetic Medicine, University of Washington, Seattle (USA) : HC Mefford
- Institute of Biochemistry and Cell Biology, Shanghai (China) : L Bao
- Laboratory of Endocrinology and Receptor Biology, NIH, NIDDK, Bethesda, Maryland (USA) : D Forrest
- Epilepsy Research Centre, University of Melbourne (Australia) : SF Berkovic, IE Scheffer
- Howard Hughes Medical Institute, University of San Francisco (USA) : LJ Ptacek

Alumni (non exhaustive)
P Cau (2000-2008) ; A Robaglia-Schlupp (2000-2008) ; S Pereira (2001-2006) ; S Jamali (2003-2007) ; N Roeckel-Trevisiol (2002-2008) ; P Roll (2002-2008) ; B Royer-Zemmour (2005-2008) ; M Ponsole-Lenfant (2006-2009) ; C Gueniot-Morizet (2009-2010) ; J Cillario (2008-2012); L Castelein (2013-2014); A Massacrier (2000-2014).

Funding / Labels

Ongoing

  • FP7: European DESIRE project, 2013-2018
  • FRC: Project “Behavioral alterations in continuous spike and waves during slow-wave sleep syndromes”, call 2013, 2015-2017
  • DHU : University-hospital department EPINEXT
  • BIOTRAIL : International PhD program

Past (non exhaustive)

  • ANR: EPILAND project, AO “Programme Blanc 2010″, SVSE-4 Neurosciences, 2010-2014
  • UCB-Pharma Partnership: EPIPHOT project, 2011-2014
  • PACA Regional Council: CERVIR project, call 2010, 2011-2013
  • National PHRC: project n°03-08, call 2010, 2011-2014
  • FRM: ‘Grands Equipements’, call 2010
  • ANR: EPICOGN project, AO “Programme Maladies rares MRAR”, 2006-2010
  • GIS/maladies rares: ‘Réarrangements Génomiques’ project, call 2006, 2007-2009
  • FFRE : ‘Interactome’ project, call 2005, 2006-2008

Join our team

Applications at various levels are welcome: Engineer schools, Master1, Master2, PhD, post-Doc, permanent researchers. Applications to be sent by email to :Pierre Szepetowski.

Publications

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