GROUP LEADERS
MOLECULAR MECHANISMS OF NEUROTRANSMITTER RELEASE
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GROUP LEADER : EL FAR Oussama

MEMBERS :

RESEARCH TOPIC :

We are mainly interested in the molecular mechanisms of synaptic transmission and neuronal excitability. Our research focuses on 3 projects:

 

1- Molecular mechanisms underlying LGI1
(Leucine-rich Glioma-Inactivated 1) mediated fine tuning of neuronal excitability


2- Activity and Receptors of Botulinum Neurotoxins


3- Synaptic transmission modulation by subunits of the vesicular V-ATPase


 

 1- Molecular mechanisms underlying LGI1 (Leucine-rich Glioma-Inactivated 1) fine tuning of neuronal excitability

LGI1 (leucine-rich, glioma-inactivated 1) is a soluble glycoprotein involved in two neurological affections: Autosomal Dominant Lateral Temporal Epilepsy (ADLTE) and certain autoimmune forms of Limbic Encephalitis (LE). In LGI1 dependent LE patients, autoimmunity is characterized by the presence of anti-LGI1 autoantibodies. In these affection, epilepsy is associated with memory loss and psychiatric disorders.

LGI1 interacts with the inactive metalloproteases ADAM22 and 23 and has been shown to be present in multi-molecular synaptic complexes including Kv1 channels and AMPA receptors. For several years, our team has been performing diagnostic tests for LGI1-dependent autoimmune LE using immunoprecipitation of Kv1 channels radio-labelled with iodinated Dendrotoxin.

Mutations in the gene coding for LGI1 mainly cause haplo-insufficiency mainly due to lack of protein secretion. Epilepsy accompanied by auditory aura characterize the majority of patients. The molecular mechanisms by which LGI1 haplo-insufficiency leads to neuronal excitability increase are poorly understood. Our data (Seagar et al., 2017) show that the neuronal excitability increase is due to a decrease in the expression of axonal Kv1 channels that play an important role in the regulation of crucial neuronal properties such as excitability, axonal conduction, and synaptic strength.

http://unis-neuro.com/maj/phototheque/photos/oussama/Neurons_et_axones_sans_Kv.jpg

2- Activity and Receptors of Botulinum Neurotoxins
Botulinum neurotoxins secreted by bacteria are responsible for human and animal botulism. It results in peripheral dysautonomia and marked potentially lethal flaccid paralysis. Moreover, these neurotoxins are of major therapeutic interest for the treatment of multiple neurological conditions.
Using laboratory-specific biological tools and a method based on Surface Plasmon Resonance, we have developed over the past ten years, rapid and ultra-efficient assays to specifically quantify the proteolytic activity of several serotypes of botulinum neurotoxins in patients sera. In collaboration with IPSEN, these tests enabled us to validate the activity of pharmaceutical batches.

http://unis-neuro.com/maj/phototheque/photos/oussama/BoNT_detection_in_patients.jpg

In collaboration with CILOA (Montpellier), we have recently developed an exosomal system allowing the expression, in a native conformation, at the surface of recombinant exosomes different membrane receptors with one or more transmembrane domains (Desplantes et al., 2017). We validated the usefulness of this methodology for the study of G-protein coupled receptors pharmacology and botulinum neurotoxin receptors.
Our current approach aims at deciphering, through cellular biology, biochemistry and modeling approaches, the molecular mechanisms that govern the recognition of botulinum neurotoxins by their neuronal receptors. We recently uncovered a directed inyteraction between the extracellular domain of synaptotagmin with gangliosides (Flores et al. 2019). We suggest that this complex represent the neuronal membrane receptor of botulinum neurotoxin type B.

 

 


3- Synaptic transmission modulation by subunits of the vesicular V-ATPase

V-ATPase (vacuolar proton ATPase) is a multimolecular nano-motor found in all eukaryotic cells. It is composed of reversibly associated two multimolecular sectors: an extra-membranous sector V1 that hydrolyzes ATP and a transmembrane sector V0 that transports protons. The primary function of this nano-motor is the active (ATP-dependent) transport of protons. It acidifies intracellular compartments and plays an important role in many physiological processes. The coupling between ATP hydrolysis and proton transport by the V-ATPase plays a crucial role in the acidification of synaptic vesicles and thus their loading in neurotransmitter molecules.

V0-sector subunits of the V-ATPase interact with SNARE proteins and independently of proton transport, a role of these subunits in modulating SNARE-dependent neurotransmitter release has emerged in recent years.

We are particularly interested in the implication of the subunits "V0c" and "V0d" in the modulation of neurotransmitter release.


https://unis-neuro.com/maj/phototheque/photos/oussama/Rosette_V0c_and_SNAREs_copie.jpg


PROJECTS :


1-
Molecular mechanisms underlying LGI1 (Leucine-rich Glioma-Inactivated 1) mediated fine tuning of neuronal excitability
We are interested in the effects of LGI1 and autoantibodies on the regulation of Kv1 channel expression and its consequences on neuronal excitability and synaptic transmission.

2-Activity and Receptors of Botulinum Neurotoxins

Our current approach aims at deciphering, through cellular biology, biochemistry and modeling approaches, the molecular mechanisms that govern the recognition of botulinum neurotoxins by their neuronal receptors.

3- Synaptic transmission modulation by subunits of the vesicular V-ATPase

We are particularly interested in the implication of the subunits "V0c" and "V0d" in the modulation of neurotransmitter release.

FUNDING :

ANR LoGik


FORMER MEMBERS :

AMENDOLA Julien, BRECHET Aline, CHAHINIAN Henri, DE SAN FELICIANO Marina , DESPLANTES Richard, DRIHEM Chiraz, ERARD-GARCIA Madeleine, GOUGOT Julie, LEVY Annie , MAULET Yves , MOUTOT Nicole , RAMIREZ FRANCO José Jorge, SAMARI Nada, VAN RENTERGHEM Catherine, YOUSSOUF Fahamoe .

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