Diagnosis and therapy

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Department of Cell Biology & Infection

Thomas Wollert - Preventing neurodegeneration by cellular recycling 

The hallmark of many neurodegenerative disorders including Parkinson’s and Alzheimer’s disease is the accumulation of toxic protein aggregates in neurons. We study cellular recycling systems that efficiently degrade such aggregates. Autophagy is one of the most versatile recycling systems in human cells but its activity decline with age. Furthermore, impaired autophagy is associated with the onset of neurodegeneration and represents a major risk factor. We investigate the interdependence of neurodegeneration and autophagy at a molecular level using innovative biophysical approaches in vitro and in vivo. We are reconstituting critical steps in autophagy in vitro from purified components to study fundamental molecular mechanisms of the pathway. The derived knowledge complements our biophysical studies of autophagy in neurons. Through this powerful combination of in vitro and in vivo approaches, we recently identified an autophagy pathway that counteracts protein aggregation in neural cells. By improving the activity of this pathway, we were able to prevent the accumulation of protein aggregates in neurons and, most importantly, to reverse protein aggregation. This study exemplifies the importance of basic research for the development of novel therapeutic approaches to treat and cure neurodegeneration.

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Marc Lecuit - Pathophysiology of central nervous system infections, a bedside-to-bench approach

Microbes can reach the central nervous system (CNS) and/or its envelopes, leading to encephalitis and meningitis. CNS infections are associated with high morbidity, mortality and long-term sequelae. Yet the etiology of up to half of CNS infections remains unknown, and the mechanisms by which microbes reach, disseminate in and induce long-term damages to the CNS are far from fully understood. We study the model bacterium Listeria monocytogenes, which in Western countries is a leading cause of encephalitis, as well as neurotropic emerging viruses, including SARS-CoV-2. Our research integrates clinical data (large cohorts of adults and children with CNS infection, MONALISA and SEAe cohorts) and experimental approaches that combine microbiology, cell biology and immunology. We are in particular interested in identifying the microbial and host factors that account for microbial invasion of and dissemination within the CNS, and for host susceptibility to central nervous system infections.

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Department of Computational Biology

Jean-Baptiste Masson - Model organism insights into neural circuit deficits 

The Decision and Bayesian Computation Unit aims at developing a new model for brain connectivity and neurodegenerative disorders, namely the drosophila larva. By combining the advanced genetic toolkits allowing single neuron addressing, optogenetic activation and inactivation of these neurons, the mapping of larva behavior onto the nervous systems, the nearly complete neural connectome (with synaptic resolution) and large scale screens of larva behavioral recordings (up to 20 000 per day), they have a unique opportunity to understand to address diseases at the scale of millions of individual. Furthermore, using electron microscopy and a virtual reality software developed in the lab, they can detect modification of small neural circuit connectivity within the larva nervous system and thus study the evolution of the disease at the synaptic scale.

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Department of Neurosciences

Thomas Bourgeron – Diagnosis and therapies for neurodevelopmental disorders 

Our group identified the first mutations associated with autism spectrum disorders (ASD) and we are currently using whole genome sequencing and deep-phenotyping data (including brain imaging) to stratify patients with ASD and neurodevelopmental disorders (NDD). Our development of genetic test pipelines are currently those used by the Plan Médecine Génomique 2025 as routine whole genome sequencing test for ASD in France. For patients mutated in SHANK3, a major gene for ASD and intellectual disability (ID), we launched a randomized clinical trial (RCT) testing lithium as a possible medication to reduce the severity of the symptoms. The RCT was delayed by the pandemic situation but should start before the end of 2021. 

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Pierre-Jean Corringer - Allosteric functioning of synaptic receptors and its regulation by pharmaceutical compounds

The scientists are working on the molecular architecture and conformational dynamics of ligand-gated ion channels that play a central role in chemical synapses. They combine to this aim structural techniques such as X-ray crystallography and cryo-EM, with electrophysiological and fluorescence approaches. The gain knowledge is used to develop original drug-design programs, notably against nicotinic acetylcholine receptors that are involved in addictive and neurodegenerative pathologies.

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Aziz El-Amraoui - Progressive sensory disorders, pathophysiology and therapy

Hearing and vision are essential for every significant activity of daily life, ranging from social interactions and mobility to an appreciation of music, art, and nature. Because of their high prevalence, untreated decline of these sensory deficits has a vast economic & societal impact, impeding communication, later leading to social isolation, depression, reduced physical and cognitive functions. Current team focus is on late onset and/or progressive forms of hearing impairment, combined or not with balance and vision deficits. More specifically, our aims include: i) understand how, despite constant use from birth onwards, our eyes and ears continue to ensure, at least for 5-6 decades, normal vision and hearing, ii) elucidate precise pathogenic features of the human neurosensory disorders using cell- and animal-based models, iii) document how external cues impact sensory decline, and iv) Evaluate and validate in vivo the delivery and efficacy of gene therapies to restore normal senses.

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Pierre-Marie Lledo - How experience and time shape brain circuits.

The Lledo laboratory has developed a multi-scale approach to understand the function and the plasticity of neuronal circuits involved in sensory perception, memory and mood control. In particular, researches are aimed at the interface between neuroscience and behavioral science to elucidate complex neural systems underlying behaviors. The team gathers neuroscientists, psychiatrists, and computational scientists to combine modern neurophysiological techniques —in vitro and in vivo awake electrophysiology, optogenetics, awake 2-photon imaging, deep-brain fiber photometry— with behavioral analysis (both human and mice) and theoretical modeling in order to monitor and manipulate neuronal circuits during behavior and in pathological contexts. The team has solid expertise in animal models and behavior, having developed a wide range of behavioral tests to evaluate sensory modalities, mood states, cognitive functions and social interactions. The scientists visualize the dynamic re-wiring of connections (triggered by adult neurogenesis) in mouse models to provide further insight for translational research into mood disorders or viral infections.

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Uwe Maskos - Nicotinic receptors and brain disease

This unit is studying nicotinic acetylcholine receptors (nAChRs) and the role of their human polymorphisms in a number of models like Alzheimer's disease, schizophrenia, and nicotine addiction. This team is specifically interested in "humanising" our models by the use of human induced pluripotent stem cells (hiPSC). 

Our approaches focussing on "diagnosis/therapy" are centred around the transplantation of human iPSC-derived neurons and non-neuronal cells into pre- and postnatal rodents. This efficient system gives us access to a human "mini-brain" that can be experimentally manipulated. The robustness of the system has already been validated in a pharmaceutical contract, testing a molecule acting on the human neurons. We will use this system to study the effects of amyloid beta, causal agent of AD, on human neurons and non-neuronal cells, like microglia, brain-resident macrophages, implicated through GWAS in AD predisposition. The approach is supported further by the arrival of a staff scientist, with long experience in iPSC work. 

This system will allow us to study the role of a human-specific gene of the nAChR family, CHRFAM7A, not found in non-human primates, linked to AD by a number of human genetic studies, and strongly expressed in human neurons, astrocytes and macrophages. 

The biomedical work will focus on the presence of human auto-antibodies to the nAChR in psychiatric patients that we have established recently. These auto-antibodies inhibit the function of the human nAChR, and can also be found in the brain of patients. This projectt initiated under the former Major Federating Program  is supported by our Laboratory of Excellence, LABEX BIO-PSY, and has access to well-documented cohorts of patients from the FondaMental foundation. This work can lead to the definition of a novel mechanism leading to pathology, as part of a growing interest worldwide in immuno-psychiatry. A clinical trial using nicotinic medication will be envisaged. 

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Christine Petit (and the Hearing Institute) - Hearing and associated disorders, from mechanisms to treatment

Exploring the neuronal network functional connectivity of auditory central pathways and cortices, associated plasticity and multimodal sensory integration as well as how they are altered by hearing deficits of genetic and non-genetic origins including those present in schizophrenia and autism... Understanding the link between auditory impairment and dementia (Alzheimer), with prospects of prevention and curing. Noise-Induced Hearing Loss, the major environmental cause of hearing loss and presbycusis (age-related hearing impairment): development of corresponding biomarkers for multiparametric diagnosis (innovative audiometric tests, brain imaging, psychoacoustics, genomics, epigenomics, other biological markers with integration by Artificial Intelligence), rationalization of clinical trials (stratification of populations) for the testing candidate therapeutic agents and search for new therapeutic agents. Gene therapy for curing monogenic severe to profound deafness. The strategy is based on a continuous back and forth movement between patients and animal models. Collaborative works in perspective with the Immunology Department.

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Department of Structural Biology & Chemistry

Pierre-Lafaye - Towards amyloid plaques and tangle imaging with nanobodies

In vivo neuroimaging of the key lesions of Alzheimer Disease (AD) (amyloid plaques, Neuro Fibrillary Tangles) is urgently needed to improve the diagnosis in clinical routine, to evaluate disease progression and to screen the effects of new drugs. The use of antibodies to detect AD lesions in vivo is limited by their weak passage of the blood brain barrier (BBB). We have previously shown that VHHs or nanobodies directed against human GFAP, an intermediate filament protein specific for astrocytes have however the potential to transmigrate across the BBB in vivo. Recently, we designed VHHs against Aß and phosphorylated-tau. These VHHs have been labelled with a fluorophore and we have shown that that they can cross the BBB and reach their target. These VHH have then been labelled with Gadolinium contrastophores in order to be used as imaging probes for plaques and tangles. We were able to perform in vitro MR imaging of amyloid plaques and tangles using these conjugates. This project is developed in close collaboration with Sylvie Bay (Unité de Chimie des Biomolécules-IP) who designed and synthesized the VHH conjugates for imaging and the overall work is also a long-term collaboration with Benoît Delatour and Charles Duyckaerts, (Institut du Cerveau et de la Moëlle Épinière, Paris) and Marc-Dhenain (MIRCen-CEA). 

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Department of Virology

Monique Lafon - Pathology of viruses that target the nervous system

Research in the Viral NeuroImmunology Laboratory aims to establish the molecular basis for the pathogenicity of viruses that infect the nervous system, such as rabies virus. The team has discovered this virus has the intriguing property to promote the survival of the neurons it infects. Elucidation of the mechanisms of action and identification of the critical domain of the viral protein that controls survival have resulted in the development of a new drug candidate for the treatment of neurodegenerative diseases such as retina diseases or Amyotrophic Lateral Sclerosis (Charcot Disease).

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