Team Van Niel

Endosomal dynamics in neuropathies

Team member : Anaïs Bécot | Pierre-Michael Coly | Mickael Couty | Maribel Lara-Corona

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Les travaux de notre équipe cherchent à mieux comprendre les mécanismes régulant la biogenèse et les fonctions de la voie endosomale dans différents types cellulaires spécialisés, in vitro et in vivo. En fonction de leur environnement et des stimuli reçus, les cellules peuvent adapter leur système endosomal pour dégrader le contenu des endosomes multivésiculaires dans les lysosomes ou pour sécréter dans le milieu extracellulaire leurs vésicules intraluminales sous forme d’exosomes. A travers nos études, nous cherchons à identifier différents mécanismes moléculaires qui régulent ces adaptations fonctionnelles et à développer différents outils pour suivre la dynamique endosomale in vitro et in vivo. Ces recherches nous permettrons de mieux comprendre le rôle de la dynamique endosomale dans différentes neuropathies et en particulier la Maladie d'Alzheimer et le développement du Gliobastome.

5 main publications

Verweij FJ, Balaj L, Boulanger CM, Carter DRF, Compeer EB, D'Angelo G, El Andaloussi S, Goetz JG, Gross JC, Hyenne V, Krämer-Albers EM, Lai CP, Loyer X, Marki A, Momma S, Nolte-'t Hoen ENM, Pegtel DM, Peinado H, Raposo G, Rilla K, Tahara H, Théry C, van Royen ME, Vandenbroucke RE, Wehman AM, Witwer K, Wu Z, Wubbolts R, van Niel G. The power of imaging to understand extracellular vesicle biology in vivo. Nature Methods. 2021 Sep;18(9):1013-1026. doi: 10.1038/s41592-021-01206-3. Epub 2021 Aug 26. PMID: 34446922 Review.(corresponding author)

Androuin A, Verweij FJ, van Niel G. Zebrafish as a preclinical model for Extracellular Vesicle-based therapeutic development. Adv Drug Deliv Rev. 2021. doi: 10.1016/j.addr.2021.05.025. Review.

Bécot A, Volgers C, van Niel G. Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation. Biomedicines. 2020 Aug 4;8(8):E272. doi: 10.3390/biomedicines8080272. PMID: 32759666 Review.

Verweij FJ, Revenu C, Arras G, Dingli F, Loew D, Pegtel DM, Follain G, Allio G, Goetz JG, Zimmermann P, Herbomel P, Del Bene F, Raposo G, van Niel G. Live Tracking of Inter-organ Communication by Endogenous Exosomes In Vivo. Dev Cell. 2019 Feb 25;48(4):573-589.e4. doi: 10.1016/j.devcel.2019.01.004. Epub 2019 Feb 7. PubMed PMID: 30745143.

van Niel G, D'Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018 Jan 17. doi: 10.1038/nrm.2017.125. [Epub ahead of print] Review. PubMed PMID: 29339798.

At the Institute of Psychiatry and Neurosciences of Paris, we use a multi-scale approach, based on the complementarity of cellular models and a model organism, the zebrafish, to better understand the role of the endosomal pathway in various neuropathies.

Within the cell, the endosomal pathway comprises a series of interconnected compartments whose primary functions are to degrade, sequester, recycle or secrete components of the plasma membrane and previously internalized extracellular elements. This pathway is involved in various pathological processes affecting the nervous system such as amyloid homeostasis and tumour migration. We are particularly interested in the degradation and secretion functions of the endosomal pathway, focusing on the multivesicular endosomes that are at the crossroads of these two functions. By merging with lysosomes, multivesicular endosomes allow catabolism and recycling of their contents and participate in cell homeostasis. By fusing with the plasma membrane, they secrete their contents into the extracellular medium, in particular vesicles called exosomes. These exosomes act as vectors of clearance and intercellular communication in all organisms. They are involved in the development of many pathologies but could also be used in clinics as biomarkers or therapeutic nano-vehicles.

The projects of our laboratory have three objectives:

The first objective is to deepen and generalize our fundamental knowledge of the intracellular mechanisms regulating the biogenesis and functions of multivesicular endosomes and exosomes. In particular, we focus on the role of membrane contact sites in lysosomal degradation and exosomal secretion processes.

The second objective is to evaluate, in parallel, the relevance of these intracellular mechanisms in nervous system cells and in an in vivo model, the zebrafish. This multi-scale approach, based on advanced imaging methods such as correlative microscopy or subcellular videomicroscopy, allows us to analyze the endosomal dynamics and biology of exosomes on live and in vivo neuronal cells.

The third objective is to combine the knowledge and tools developed in the first two objectives in order to evaluate their relevance in the development but also the treatment of different neuropathies, such as Alzheimer's disease and glioblastoma.

Figure : Schematic model of the role of endosomal dynamics

Our studies focus on the role of the endosomal pathway in the development of neuropathies such as Alzheimer's disease and glioblastoma. In this context, we are seeking to better understand the mechanisms that regulate the degenerative (via lysosomes) and secretory (via exosomes) functions in neuronal cells. To do this we rely on advanced imaging techniques and the development of new molecular tools in a model organism, zebrafish and cell cultures.
Merci

Team Members

Guillaume Van Niel

Since 1998, Guillaume van Niel has investigated exosomes and their compartment of origin, multivesicular bodies. During his Ph.D at the Necker institute (Paris, France), he reported and investigated the secretion and the function of exosomes secreted by intestinal epithelial cells. In 2003 at the Utrecht medial center (Utrecht, the Netherlands) he demonstrated ubiquitination of MHC II molecules, a key post-translational modification for sorting to multivesicular bodies in dendritic cells. In 2005 he joined the Curie Institute (Paris, France) and obtained a CNRS permanent position in this team in 2008 to investigate the biogenesis of multivesicular bodies in pigment cells. He notably reported the role of intraluminal vesicles in the generation of physiological amyloid fibrils. Since 2017 he is team leader at the Intitute of Psychiatry and Neurosciences of Paris (Paris, France) developing new tools to visualize exosomes, notably in vivo, and to understand the role of endosomal dynamic between degradation and secretion in amyloid associated pathologies. He has a strong expertise in the cell biology of exosomes and uses extensively different techniques of imaging among which electron microscopy.

Pierre-Michaël Coly

Pierre-Michaël Coly completed his PhD (2013-2017) in the “Neuronal and Neuroendocrine Differentiation and Communication” laboratory (Inserm U982, Rouen). Under the supervision of Dr Fabrice Morin and Pr Pierrick Gandolfo, he focused on the role of the autophagic process in the migration of glioblastoma cells induced by chemotactic GPCRs. He was able to show that the activation of these GPCRs led to an inhibition of autophagy at the migration front, thus allowing the formation of focal adhesion complexes. He then conducted his postdoctoral work at the Paris Cardiovascular Research Center (Inserm U970) in the team of Dr Chantal Boulanger. In the context of atherosclerosis, he studied the impact of an autophagy defect on the composition of endothelial extracellular vesicles, as well as the role of these vesicles in the spread of the pathology. During this period, he co-supervised the thesis work of a doctoral student seeking to restore functional endothelial autophagy to limit inflammation and slow the formation of atherosclerotic plaques in vivo. In 2021 Pierre-Michaël joined the laboratory of Dr Guillaume van Niel where he focuses on developing tools to modulate the secretion of extracellular vesicles in vitro and in vivo, as well as applying these tools to understand the role of extracellular vesicles in the progression of glioblastoma.

Alexandre Androuin

After earning a Doctor of Pharmacy (PharmD) degree in 2015, Alexandre Androuin carried out a research thesis in neuroscience in the Alzheimer’s disease and prion diseases team of Dr Marie-Claude Potier within the Brain and Spine Institute (ICM) in Paris. Under the supervision of Dr. Serge Marty, he obtained his PhD in neuroscience in 2018, which focused on the study of alterations in synapses and neuronal cell bodies in Alzheimer’s disease and in a transgenic mouse model of amyloid pathology. The aim of this project was to characterize these alterations with electron microscopy, to evaluate their functional consequences on physiology and memory capacities in this model, and finally to study their mechanisms and the effect of different pharmacological treatments. Alexandre then pursued a post-doctoral project under the supervision of Dr. Susana Boluda and Dr. Benoît Delatour on the study of the role of tau strains in phenotypic variability in Alzheimer’s disease in vitro and in vivo. In 2021, he joined the team of Dr Guillaume van Niel in the Institute of Psychiatry and Neurosciences of Paris (IPNP). The aim of his project is to develop a zebrafish model of Alzheimer’s disease in order to visualize and study the involvement of extracellular vesicles in the propagation of toxic proteins in the brain in vivo. His project also aims to develop a high-throughput screening of molecules using in vivo imaging in zebrafish.

Anaïs Bécot

Anaïs Bécot completed her PhD (2016-2019) at the Institute of Molecular and Cellular Pharmacology (IPMC) in Sophia-Antipolis (France), under the supervision of Dr. Inger Lauritzen and Dr. Frédéric Checler who are interested in the role of APP metabolites in the Alzheimer's disease pathological mechanisms. Anaïs focused on the study of the APP-CTFb fragment, whose intraneuronal accumulation is associated with endosomal-lysosomal-autophagic defects appearing early in Alzheimer's patients. In a first project, she tested the efficacy of the activation of the lysosomal-autophagic system in in vitro and in vivo models of Alzheimer's disease, with the aim of reducing the levels of APP-CTFb and associated pathological phenotypes. In a second project, she investigated the role of APP-CTFb in the spreading of the disease in the brain by studying a type of extracellular vesicle, the exosomes. This work revealed the enrichment of APP-CTFb oligomeric forms in exosomes released by Alzheimer's model cells, as well as a link between oligomerization and g-secretase activity. In May 2020, she joined the team of Dr. Guillaume van Niel where she is studying the mechanisms involved in the balance between endolysosomal degradation and exosomal secretion. Her project focuses in particular on the effect of apolipoprotein E particles on endolysosome trafficking and exosome secretion by modulating the formation of membrane contact sites.

Vincenzo Verdi

Vincenzo Verdi graduated in 2015 in Medical Biotechnologies and Molecular Medicine at University of Palermo (Italy). His research experience started in 2014 at the Department of Biopathology and Medical Biotechnologies in Palermo in Prof. Riccardo Alessandro’s team, working on the autocrine role of extracellular vesicles (EVs) in Chronic Myeloid Leukemia cell lines. After, Vincenzo got a 2 years-internship at the Department of Biomedicine and Clinical Neurosciences (University of Palermo) in Prof. Natale Belluardo’s team, carrying on studies on the transactivation of FGFR1 by Muscarinic Acetylcholine Receptors in hippocampal neurons in vitro and the effects of Oxotremorine as axiolitic/ antidepressant in vivo in chronic restraint-stress (CRS) mice and rats models . In 2016 he obtained a PhD position in "Neurosciences" at Scuola Normale Superiore in Pisa, where he joined the “Intrabody Lab” of Prof. Antonino Cattaneo working on "in cell- epitope mapping" in S. cerevisiae of ScFV intrabodies selected against Neuroligin-1/2. In July 2018 he quitted this position and came back to the EVs’ field joining back the group of Prof. Riccardo Alessandro in Univ. of Palermo as research volunteer, performing studies on Ankylosing Spondilytis patients sera- derived EVs in monocytes differentiation.

From January 2020 Vincenzo Verdi is a member of proEVLifeCycle Consortium as Marie Skłodowska-Curie ITN PhD Fellow and part of Dr. Guillaume van Niel’s team. He is currently developing molecular tools to redirect and manipulate the fate of Prostate Cancer- derived EVs in vivo, studying their role in the recipient cells and exploiting Zebrafish (Danio rerio) as a valid model to investigate tumor exosomal dynamics in real- time.

LinkedIn profile link : https://it.linkedin.com/in/vincenzo-verdi-a18b66106

Maribel Lara Corona

Maribel Lara Corona obtained her Engineer Diploma in Biotechnology in 2016 in Toluca, Mexico. During this time, she participated in a project concerning the alternative splicing of genes encoding insulin and dopamine receptors at INMEGEN in Mexico City under the supervision of Dr. Eréndira Avendaño Vázquez.

She obtained her Master diploma in Molecular and Cellular Biology at the University of Paris in 2020. During her studies, she worked in the role of BACE1 in endosomal homeostasis and lysosomal degradation under the co-supervision of Dr Guillaume van Niel at the IPNP and Dr Stéphanie Miserey at Marie Curie Institute.

Since February 2021, she rejoined Dr. van Niel’s lab to do her PhD. There, she studies the properties of engineered exosomes to improve their use as drug nanovehicles, working with the zebra fish as model organism to highlight its use as a preclinical in vivo model.

Mickaël Couty

Mickaël Couty obtained his Master's degree in Health Biology at the University of Paris-Est Créteil (UPEC, France) where he studied tissue, cell and gene biotherapies. During his Master internship he has worked on the resistance mechanisms of urogenital cancers and on the mechanisms of cell death of prostate tumors in response to a targeted therapy combining a hormone with Dermaseptin B2 (DRS-B2)and a cationic antimicrobial peptide derived from biodiversity with anti-tumor and anti-proliferative activity.

After graduating in 2019, he joined Dr. Chantal Boulanger's team at the Paris Cardiovascular Research Center (PARCC, Paris, France) as an engineer under the supervision of Dr. Olivier Blanc-Brude. In the context of sickle cell disease, he studied the expression of a family of proteins in peripheral blood cells and in extracellular vesicles released into the blood.

Finally, he joined in July 2020 the Institute of Psychiatry and Neurosciences of Paris (Paris, France) where he studies in vivo trafficking of exosomes during development of glioblastoma in the zebrafish model.

Amandine Robac

In 2020, Amandine Robac obtained her Master's degree in Neuroscience at the University of Rouen Normandie (France) where she studied the nervous system and its relationship with other organs from a molecular, cellular, and behavioral point of view, both in physiological and pathological conditions.

Following her graduation, Amandine joined Dr. Nicolas Guérout's team at the EA3830 of the University of Rouen to study and implement therapeutic strategies in murine models for traumatic spinal cord injury.

Finally, in 2022, she joins the Institute of Psychiatry and Neurosciences of Paris (Paris, France), in Dr. van Niel's team as an engineer in biological experimentation and instrumentation. She oversees generating and maintaining the different strains of zebrafish (Danio rerio) necessary for the whole team, using crossbreeding and/or microinjection of plasmids into zebrafish embryos, to better understand the role of extracellular vesicles in inter-organ communication in vivo.