Synaptopathies and autoantibodies (SYNATAC)

Principal investigator: Jérôme HONNORAT

Autoimmune encephalitis | NMDA receptor | VEGF | Paraneoplastic neurological syndromes | Glial cells | Synaptic proteins

 The goal of our research is to better understand the cellular and molecular mechanisms involved in neuronal and synaptic dysfunctions in neuropsychiatric diseases.

We are particularly interested in the pathophysiology of autoimmune encephalitis (AE) and paraneoplastic neurological syndromes (PNS). These neuropsychiatric diseases are associated with autoantibodies present in patients’ serum and CSF, which target neuronal proteins involved in synaptic transmission (ie, NMDAR, AMPAR, GABABR), synapse organization (LGI1, CASPR2), or signaling (DPPX, CRMP). Each of these autoantibodies is associated with a clinical syndrome similar to what is observed when these same proteins are disrupted by pharmacological or genetic means. These autoantibodies have an impact on the structure and function of the antigens they target. Our strategy is to integrate basic and clinical research to study the mechanism of action of autoantibodies and their effects on synaptic and neuronal functions and associated neuro-inflammatory processes. We study synaptic functions in a physiological and pathological context, using patient autoantibodies as research tools. We focus in particular on NMDA receptors and some of their partners, such as VEGFR2, and on proteins involved in neuronal excitability, such as LGI1 or CASPR2. We have developed animal models with autoantibody infusion in the hippocampus via osmotic pumps, and in vitro models of neuronal primary cultures and organotypic brain slices. The use of these different models allows us to study the effect of the inflammatory response on neurons and glial cells, the transport of glutamate, and the modulation of neurotransmission.

Our biological collection of serum and CSF from SNP and EA patients allows us to detect autoantibodies targeting unknown proteins or neuronal receptors. A translational approach is then used to identify the targeted proteins and understand their roles. These new targets can also serve as biomarkers of the disease and contribute to the development of new therapeutic strategies.

This work should lead to a better understanding of neuropsychiatric diseases associated with autoantibodies, but also of neurodegenerative pathologies such as Alzheimer’s disease.

RHU BETPSY

BETPSYThe BETPSY project, coordinated by Prof. Honnorat, has received a 7.3 million euro “Future Investment Program (PIA)” funding. It is based on the collaboration of 5 academic research teams (UCBL, HCL, ICM, CLB and INSERM), and an industrial partner (Euroimmun), specialized in the development and marketing of autoantibody detection kits.

The aim of the BETPSY project is to better characterize EA and SNPs in order to improve the care and treatment of patients suffering from these diseases, through the identification of new biomarkers, the understanding of the mechanisms involved in these autoimmune diseases and the development of animal models: https://www.rhu-betpsy.fr/

Team Members

  • Jerome HONNORATProfessor, UCBL, HCL – jerome.honnorat@chu-lyon.fr – 04 26 67 28 01
  • Lucie ALIOUANEResearcher, UCBL – lucie.aliouane@univ-lyon1.fr – 04 72 35 78 13
  • Jean-Christophe ANTOINEProfessor, CNRS – j.christophe.antoine@chu-st-etienne.fr – 04 77 12 78 05
  • Sarah BENKEDERPhD student, INSERM – sarah.benkeder@univ-lyon1.fr – 04 26 67 28 01
  • Roger BESANCONAssociate Professor, UCBL – roger.besancon@univ-lyon1.fr – 04 26 67 28 01
  • Nadia BOUTAHARAssociate Professor, CNRS – nadia.boutahar@chu-st-etienne.fr – 04 77 82 83 10
  • Pauline BOUVETPhD student, INSERM – pauline.bouvet@univ-lyon1.fr – 04 26 67 28 01
  • Jean-Philippe CAMDESSANCHEProfessor, CNRS – j.philippe.camdessanche@chu-st-etienne.fr – 04 77 12 05 59
  • Naura CHOUNLAMOUNTRIResearch Assistant, CNRS – naura.chounlamountri@univ-lyon1.fr – 04 26 67 28 01
  • Sterenn CLOSSResearcher, CNRS – sterenn.closss@chu-lyon.fr –
  • Kassandre COMBETPhD student, CNRS – Kassandre.combet@univ-lyon1.fr – 04 26 67 28 01
  • Priscille DE GEAPhD student, CNRS – priscille.de-gea@univ-lyon1.fr – 04 26 67 28 01
  • Virginie DESESTRETProfessor, CNRS – virginie.desestret@univ-lyon1.fr –
  • Le Duy DOResearcher, CNRS – le-duy.do@univ-lyon1.fr – 04 26 67 28 01
  • Fabrice FAUREResearch Assistant, CNRS – fabrice.faure@univ-lyon1.fr – 04 26 67 28 01
  • Bastien JOUBERTAssociate Professor, CNRS – bastien.joubert@chu-lyon.fr –
  • Mathilde MILLOTResearcher, CNRS – –
  • Claire MEISSEREL — CVResearcher, INSERM – Claire.meissirel@inserm.fr – 04 26 67 28 01
  • Christian MORITZResearcher, CNRS – christian.moritz@univ-st-etienne.fr –
  • Olivier PASCUAL CVResearcher, INSERM – olivier.pascual@inserm.fr – 04 26 68 82 74
  • Veronique PELLIER-MONINAssociate Professor, UCBL – veronique.pellier-monnin@univ-lyon1.fr – 04 26 67 28 01
  • Géraldine PICARDResearcher, HCL – geraldine.picard@chu-lyon.fr –
  • Elise PETERResearcher, UCBL – –
  • Antonio FARINAResearcher, HCL – antoniofarina100791@gmail.com –
  • Macarena GARCIAResearcher, INSERM – ext-macarena.villagran@chu-lyon.fr –
  • Anne-Laurie PINTOResearcher, HCL – anne-laure.pinto@chu-lyon.fr –
  • Mélisse ROBERTPhD student, HCL – melisse.robert@univ-lyon1.fr – 04 26 67 28 01
  • Veronique ROGEMONDResearcher, HCL – veronique.rogemond@chu-lyon.fr – 04 72 35 58 40
  • Yannick THOLANCEAssociate Professor, UCBL – Yannick.Tholance@chu-st-etienne.fr –
  • MArine VILLARDResearcher, HCL – marine.villard@chu-lyon.fr –
  • Clementine VINCENTPost-doc, INSERM – clementine.vincent@univ-lyon1.fr – 04 26 67 28 01
  • Valentin WUCHERPost-doc, UCBL – valentin.wucher@univ-lyon1.fr – 04 26 73 94 04

Selected publications

  1. Glial Fibrillary Acidic Protein Autoimmunity: A French Cohort Study
    Gravier-Dumonceau A, Ameli R, Rogemond V, Ruiz A, Joubert B, Muñiz-Castrillo S, Vogrig A, Picard G, Ambati A, Benaiteau M, Rulquin F, Ciron J, Deiva K, de Broucker T, Kremer L, Kerschen P, Sellal F, Bouldoires B, Genet R, Biberon J, Bigot A, Duval F, Issa N, Rusu EC, Goudot M, Dutray A, Devoize JL, Hopes L, Kaminsky AL, Philbert M, Chanson E, Leblanc A, Morvan E, Andriuta D, Diraison P, Mirebeau G, Derollez C, Bourg V, Bodard Q, Fort C, Grigorashvili-Coin I, Rieul G, Molinier-Tiganas D, Bonnan M, Tchoumi T, Honnorat J, Marignier R
    Neurology (2022) — Show abstract
  2. Familial autoimmunity in neurological patients with GAD65 antibodies: an interview-based study
    Muñiz-Castrillo S, Vogrig A, Montagnac C, Joubert B, Benaiteau M, Casez O, Chaumont H, Hopes L, Lanoiselée HM, Navarro V, Thomas B, Ursu R, Gonçalves D, Fabien N, Ducray F, Julier C, Honnorat J
    Journal of neurology (2021) — Show abstract
  3. Distinctive clinical presentation and pathogenic specificities of anti-AK5 encephalitis
    Muñiz-Castrillo S, Hedou JJ, Ambati A, Jones D, Vogrig A, Pinto AL, Benaiteau M, Broucker T, Fechtenbaum L, Labauge P, Murnane M, Nocon C, Taifas I, Vialatte de Pémille C, Psimaras D, Joubert B, Dubois V, Wucher V, Desestret V, Mignot E, Honnorat J
    Brain (2021) — Show abstract
  4. Multimodal Imaging with NanoGd Reveals Spatiotemporal Features of Neuroinflammation after Experimental Stroke
    Hubert V, Hristovska I, Karpati S, Benkeder S, Dey A, Dumot C, Amaz C, Chounlamountri N, Watrin C, Comte JC, Chauveau F, Brun E, Marche P, Lerouge F, Parola S, Berthezène Y, Vorup-Jensen T, Pascual O, Wiart M.
    Adv Sci (Weinh) (2021) — Show abstract
  5. Immunopathogenesis and proposed clinical score for identifying Kelch-like protein-11 encephalitis
    Vogrig A, Péricart S, Pinto AL, Rogemond V, Muñiz-Castrillo S, Picard G, Selton M, Mittelbronn M, Lanoiselée HM, Michenet P, Benaiteau M, Pariente J, Zéphir H, Giordana C, Montaut S, Salhi H, Bachoumas P, Montcuquet A, Letovanec I, Uro-Coste E, Honnorat J
    Brain communications (2021) — Show abstract
  6. Argonaute Autoantibodies as Biomarkers in Autoimmune Neurologic Diseases
    Do LD, Moritz C, Muñiz-Castrillo S, Pinto AL, Tholance Y, Brugiere S, Couté Y, Stoevesandt O, Taussig MJ, Rogemond V, Vogrig A, Joubert B, Ferraud K, Camdessanché JP, Antoine JC, Honnorat J
    Neurol Neuroimmunol Neuroinflamm (2021) — Show abstract
  7. Clinical and Prognostic Value of Immunogenetic Characteristics in Anti-LGI1 Encephalitis
    Muñiz-Castrillo S, Haesebaert J, Thomas L, Vogrig A,  Pinto AL, Picard G, Blanc C, Do LD, Joubert B, Berzero G, Psimaras D, Alentorn A, Rogemond V, Dubois V, Ambati A, Tamouza R, Mignot E, Honnorat J
    Neurol Neuroimmunol Neuroinflamm (2021) — Show abstract
  8. Microglia modulate gliotransmission through the regulation of VAMP2 proteins in astrocytes
    Takata-Tsuji F, Chounlamountri N, Do LD, Philippot C, Novion Ducassou J, Couté Y, Ben Achour S, Honnorat J, Place C, Pascual O.
    Glia (2021) — Show abstract
  9. VEGF counteracts amyloid-β-induced synaptic dysfunction
    Martin L, Bouvet P, Chounlamountri N, Watrin C, Besançon R, Pinatel D, Meyronet D, Honnorat J, Buisson A, Salin PA, Meissirel C.
    Cell Rep (2021) — Show abstract
  10. Anti-CASPR2 clinical phenotypes correlate with HLA and immunological features
    Muñiz-Castrillo S, Joubert B, Elsensohn ME, Pinto AL, Saint-Martin M, Vogrig A, Picard G, Rogemond V, Dubois V, Tamouza R, Maucort-Boulch D, Honnorat J
    J Neurol Neurosurg Psychiatry (2020) — Show abstract
  11. Ketamine/xylazine and barbiturates modulate microglial morphology and motility differently in a mouse model
    Hristovska I, Verdonk F, Comte JC, Tsai ES, Desestret V, Honnorat J, Chrétien F, Pascual O.
    PLoS One (2020) — Show abstract
  12. Structural mapping of hot spots within human CASPR2 discoidin domain for autoantibody recognition
    Liang W, Zhang J, Saint-Martin M, Xu F, Noraz N, Liu J, Honnorat J, Liu H.
    J Autoimmun (2019) — Show abstract
  13. Impact of anti-CASPR2 autoantibodies from patients with autoimmune encephalitis on CASPR2/TAG-1 interaction and Kv1 expression
    Saint-Martin M, Pieters A, Déchelotte B, Malleval C, Pinatel D, Pascual O, Karagogeos D, Honnorat J, Pellier-Monnin V, Noraz N.
    J Autoimmun (2019) — Show abstract
  14. Contactin-associated protein-like 2, a protein of the neurexin family involved in several human diseases
    Saint-Martin M, Joubert B, Pellier-Monnin V, Pascual O, Noraz N, Honnorat J.
    Eur J Neurosci (2018) — Show abstract
  15. Antifibroblast growth factor receptor 3 antibodies identify a subgroup of patients with sensory neuropathy
    Antoine JC, Boutahar N, Lassablière F, Reynaud E, Ferraud K, Rogemond V, Paul S, Honnorat J, Camdessanché JP
    Neurol Neurosurg Psychiatry (2015) — Show abstract

Funding & Support

  • Ministry of Health: Reference center on rare diseases. Autoimmune encephalitis and paraneoplastic neurological syndromes.
  • Inca: Protéines de guidage axonal et tumeurs neuroendocrines gastro-entero-pancréatiques: rôle dans la progression tumorale
  • ANR: Identification de biomarqueurs diagnostiques, physiopathologiques, pronostiques et de progression des troubles
  • ANR-PRTS: MECANO : Mechanisms of autoimmune encephalitis
  • FRC: Mechanisms of autoimmune abnormal behaviour
AFM Téléthon
Agence Nationale de la Recherche
AFM Téléthon