NeuroGenetics and Physiology

Co-Leaders

Research center

47 bld de l'Hôpital
75651 Paris
Alexis Brice

Institution

Inserm
CNRS
Université Pierre et Marie Curie
ED158
Université Pierre et Marie Curie

Laboratory

Phone: 01 42 16 19 61
UMRS 1127 UMR 7225
IHU A-ICM, Neuratris, Institut Carnot ICM

Mots clefs

Alzheimer’s disease
Neuroinflammation
Multiple Sclerosis
neuromuscular junction
human genetics
Available to host a PhD student

publications

ImmunoChip study implicates antigen presentation to T cells in narcolepsy. Faraco J, Lin L, Kornum BR, Kenny EE, Trynka G, Einen M, Rico TJ, Lichtner P, Dauvilliers Y, Arnulf I, Lecendreux M, Javidi S, Geisler P, Mayer G, Pizza F, Poli F, Plazzi G, Overeem S, Lammers GJ, Kemlink D, Sonka K, Nevsimalova S, Rouleau G, Desautels A, Montplaisir J, Frauscher B, Ehrmann L, Högl B, Jennum P, Bourgin P, Peraita-Adrados R, Iranzo A, Bassetti C, Chen WM, Concannon P, Thompson SD, Damotte V, Fontaine B, Breban M, Gieger C, Klopp N, Deloukas P, Wijmenga C, Hallmayer J, Onengut-Gumuscu S, Rich SS, Winkelmann J, Mignot E, PLoS genetics, 2013 Feb.

Constitutive activation of the calcium sensor STIM1 causes tubular-aggregate myopathy. Böhm J, Chevessier F, Maués De Paula A, Koch C, Attarian S, Feger C, Hantaï D, Laforêt P, Ghorab K, Vallat JM, Fardeau M, Figarella-Branger D, Pouget J, Romero NB, Koch M, Ebel C, Levy N, Krahn M, Eymard B, Bartoli M, Laporte J, American journal of human genetics 2013-Feb-7.

A mutation causes MuSK reduced sensitivity to agrin and congenital myasthenia. Ben Ammar A, Soltanzadeh P, Bauché S, Richard P, Goillot E, Herbst R, Gaudon K, Huzé C, Schaeffer L, Yamanashi Y, Higuchi O, Taly A, Koenig J, Leroy JP, Hentati F, Najmabadi H, Kahrizi K, Ilkhani M, Fardeau M, Eymard B, Hantaï D. PloS one 2013-01

Krabbe disease in adults: phenotypic and genotypic update from a series of 11 cases and a review.Debs R, Froissart R, Aubourg P, Papeix C, Douillard C, Degos B, Fontaine B, Audoin B, Lacour A, Saïd G, Vanier MT, Sedel F. Journal of inherited metabolic disease 2012-Nov-30

Determination of the real effect of genes identified in GWAS: the example of IL2RA in multiple sclerosis.Babron MC, Perdry H, Handel AE, Ramagopalan SV, Damotte V, Fontaine B, Müller-Myhsok B, Ebers GC, Clerget-Darpoux F. European journal of human genetics : EJHG. 2012-Mar.

Fields of research

Neurological and psychiatric diseases

Research Theme

Notre équipe a la particularité d’être multithématique, avec trois thèmes de recherche.Notre premier objectif (IP : S NICOLE et D HANTAI) est d’étudier les pathologies humaines avec anomalies de l’excitabilité membranaire qui associent les canalopathies musculaires, les syndromes myasthéniques congénitaux et les pathologies associées ( hyperexcitabilité nerveuse périphérique, neuropathie thermosensible, hémiplégie alternante de l’enfant). Une partie de nos travaux est transversale et consiste à développer des outils cliniques, neurophysiologiques et moléculaires pour le diagnostic médical. La seconde partie est plus fondamentale et a pour but d’étudier la physiopathologie de ces maladies en utilisant des modèles in vitro et in vivo.Notre second projet (IP : C. Delarasse) est d’étudier le rôle de facteurs qui pourraient affecter le cours de la maladie d'Alzheimer (MA), tels que les processus neuro-inflammatoires et la voie non-amyloïdogénique. Notre recherche se concentre sur le rôle du récepteur purinergique P2X7R dont l’expression est augmentée autour des lésions chez les patients atteints de MA et qui est impliqué dans ces processus.Nos derniers travaux portent sur la génétique de la sclérose en plaques (IP : B. FONTAINE et I. REBEIX) portent sur l’identification récente de 52 facteurs génétiques de prédisposition à la sclérose en plaques par criblage anonyme du génome dans le cadre du consortium international (IMSGC). Une de nos études porte sur l’interaction génétique au sein du réseau « molécules d’adhésion » dans la prédisposition à la maladie. Les autres projets visent à préciser la localisation et la nature des facteurs identifiés par étude de l’ « exome » et de la charge de susceptibilité individuelle ou de groupes de patients.

Lab rotation

Dendritic cells in the pathophysiology of Multiple Sclerosis

Chercheur responsable: 

FONTAINE Bertrand

Dates: 

1 September 2016 - 31 December 2016

Date limite de candidature: 

1 September 2016

Lab rotation proposal

~ Sep-Dec 2016 ~ Jan-March 2017 ~ Apr-June 2017

Project:

In multiple sclerosis (MS), deregulated T lymphocyte responses are involved in the attack and destruction of myelin in the central nervous system (CNS) leading to neuro-degeneration and irreversible disability. One of the crucial stages in the pathophysiology of MS is the massive CNS infiltration of pathogenic cells that are reactivated in situ by antigen presenting cells (APC), either CNS resident such as perivascular macrophages and microglia or systemic (dendritic cells, macrophages).As part of an international consortium, our team has participated in the identification of 110 genetic polymorphisms involved in MS susceptibility. For each of the polymorphisms site, it was determined the most likely gene involved in MS predisposition and the results confirm the key role of immune dysfunction [1, 2]. Among the 110 genes identified, 55 are involved in the process of differentiation and functions of immune cells and in particular 23 of them have an essential role in the biology of myeloid cells.These results suggest that the genetic susceptibility to MS is due to a global dysfunction of cells of the myeloid lineage.To test this hypothesis, we have stratified a cohort of 3000 MS patients and 800 control subjects according to their genetic load in the 23 polymorphisms associated with myeloid cells functions. From this stratified cohort, the proposed M2 project aims to characterize the phenotype and functional activity of dendritic cells (DCs) differentiated from MS patients blood precursors with a strong genetic load in these polymorphisms, in direct comparison with DCs from MS patients not having this genetic load and with DCs from control subjects. To perform this project the candidate will use cell culture and immunological methods both in vitro and in vivo.

1  Sawcer, S., Hellenthal, G., Pirinen, M., Spencer, C. C., Patsopoulos, N. A., Moutsianas, L., Dilthey, A.et al., Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011. 476: 214-219.2 International Multiple Sclerosis Genetics, C., Beecham, A. H., Patsopoulos, N. A., Xifara, D. K., Davis, M. F., Kemppinen, A., Cotsapas, C.et al., Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet 2013. 45: 1353-1360.

Address: Institut Du Cerveau et de la Moelle Épinière - 47 bld de l'Hôpital 75651 Paris

Phone number: +33 157274413 ; Emailmohamed.elbehi@icm-institute.org

Website



Superviseur: 

Mohamed EL BEHI

Wnt signaling at the neuromuscular junction

Chercheur responsable: 

FONTAINE Bertrand

Dates: 

1 September 2016 - 31 December 2016

Date limite de candidature: 

1 September 2016

Lab rotation proposal: 3 months

~ Sep-Dec 2016 ~ Jan-March 2017 ~ Apr-June 2017

Project:

Neuromuscular junction development requires a temporally fine-tuned balance of distinct signaling activities initiated from muscle or motoneuronal-secreted molecules. Any disruption of these signaling activities drastically affects NMJ formation and maintenance and may lead to neuromuscular diseases. Recent data from the literature emphasize the role of Wnts molecules in NMJ formation and maintenance. The aim of this research project is (1) to investigate the functional role of Wnts molecules and their associated signaling pathways in NMJ formation and maintenance; (2) to test the therapeutic effect of pharmacological reagents, modulators of the Wnt signaling pathway in neuromuscular disorders. Our team has recently generated a transgenic mouse bearing the deletion of the Wnt binding domain (CRD) of the tyrosine kinase receptor called MuSK, a central player in NMJ formation. MuSK CRD deletion causes significant defects of innervation and leads to a pathogenic phenotype in adult mice (Messéant et al., 2015). Using this mouse model as well as other mouse lines, we will characterize and study the Wnt signaling pathways involved in NMJ formation and maintenance and test the beneficial effect of pharmacological reagents modulators of the Wnt signaling pathways. To realize this project, the student will use biochemistry and cell biology approaches both in vitro (muscle cell culture) and in vivo (transgenic mice lines). He will be supervised by a chargé de recherche INSERM, holding an HDR.

AddressInstitut Du Cerveau et de la Moelle Épinière - 47 bld de l'Hôpital 75651 Paris

Phone number: +33 1 57 27 44 04 ; EmailLaure.strochlic@inserm.fr

Website

Superviseur: 

Laure STROCHLIC

Inflammation in Alzheimer’s disease

Chercheur responsable: 

FONTAINE Bertrand

Dates: 

1 September 2016 - 31 December 2016

Date limite de candidature: 

1 September 2016

Lab rotation proposal

~ Sep-Dec 2016 ~ Jan-March 2017

Project:

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by formation of β-amyloid plaques, neurofibrillary tangles and neuronal cell death leading to progressive dementia.  The exact processes that cause AD are still poorly understood. Recent data indicate that microglia (the resident immune cell of the central nervous system) is a key player in the pathological processes in AD. β-amyloid plaques are surrounded by many activated microglial cells and astrocytes. Furthermore, many susceptibility genes identified are associated with innate immune functions. However, the innate immune system plays complex roles that need to be clearly defined in AD. The aim of our project is to study the role of innate immune cells in AD and the involvement of inflammatory pathways on the development of the disease, in particular the role of purinergic receptor. Our project will give us a more comprehensive approach of pathway modifications in AD which will allow us to discriminate beneficial inflammatory pathways from pathogenic ones. Targeting key element affecting microglia activity would improve the progression of AD. Therapeutic molecules identified will be validated in AD transgenic models.

AddressInstitut Du Cerveau et de la Moelle Épinière - 47 bld de l'Hôpital 75651 Paris

Phone number: +33 1 57 27 44 01 ; Emailcecile.delarasse@upmc.fr

Website

Superviseur: 

Cécile DELARASSE

Zebrafish models of congenital neuromuscular diseases

Chercheur responsable: 

FONTAINE Bertrand

Dates: 

1 September 2016 - 31 December 2016

Date limite de candidature: 

1 September 2016

Lab rotation proposal:

~ Sep-Dec 2016 ~ Jan-March 2017 

Project:

Congenital myasthenic syndromes (CMS) and periodic paralyses (PP) are two monogenic groups ofneuromuscular diseases with muscle weakness as main clinical sign. They result from defective neuromuscular transmission and propagation of the action potential in the skeletal muscle fiber in response to motor neuron signals, respectively. If advances in the knowledge of PP and CMS pathophysiology have been spectacular in the last years, critical issues remain to be resolved such as the origin of the secondary pathological events worsening the phenotype in PP, the participation of the central nervous system in the disease development for some types of CMS, and the fluctuation of the phenotype and the development of more personalized and efficient therapies for the two. One powerful animal model to explore neurological disorders is zebrafish. In this species, developmental and adult stages can be explored at the behavioural, morphological, and electrophysiological levels to investigate the physiological properties of motor neurons and the muscle fibers they innervate. The project aims to determine whether we can reproduce PP and CMS in genetically-engineered mutant lines of zebrafish. Targeted mutant zebrafish lines are currently under development to introduce missense mutations in the skeletal muscle sodium or calcium channels responsible for PP, and in motor neuronal genes responsible for peculiar types of CMS. The mutant fishes will be phenotypically investigated in order to determine whether they displayed the expected phenotypes. This project will eventually help to dissect the pathophysiological mechanisms leading to phenotypic fluctuation in PP and CMS and to provide us with an efficient animal model to conduce preclinical proof of principle for new emerging candidate drugs.

Address: Institut Du Cerveau et de la Moelle Épinière - 47 bld de l'Hôpital 75651 Paris

Phone number: + 33 (0)1 57 27 44 01 ; Email:sophie.nicole@inserm.fr

 

Superviseur: 

Sophie NICOLE