Neurodegenerative Diseases​

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Department of Cell Biology & Infection

Sandrine Etienne-Manneville - Astrocytic responses to inflammatory situations

Astrocytes form the majority of glial cells of the central nervous system. They play a key role in brain homeostasis, they serve as physical and nutritional support for neurons and they directly participate in synaptic transmission. In inflammatory situations, such as those induced by infections, traumas, autoimmune and neurodegenerative diseases and cancer, astrocytes undergo a reaction called astrogliosis, which is often detrimental to neuroregeneration. Astrogliosis is associated with changes in cell shape and polarity, proliferation and migration together with changes in protein expression.

The Cell Polarity, Migration and Cancer group aim to identify the keys factors controlling to astrogliosis to eventually limit this reaction. We have shown that GFAP a glial intermediate filament protein overexpressed during astrogliosis plays a crucial role in astrocyte polarization and migration. Modulating GFAP-mediated cell responses paves the way to new therapeutic strategy to modulate astrogliosis and its consequences in inflammatory situations.

In addition, we develop a project on Alexander disease, a leukodystrophy characterized by abnormal protein deposits known as Rosenthal fibers. This genetic disorder is caused by GFAP mutations which leads to the disorganization of the intermediate filament network. We investigate the consequence of these mutations on astrocyte behaviour during the disease. 

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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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Chiara Zurzolo - Mechanisms of intercellular communication in the brain and role in the progression of neurodegenerative diseases

Neurodegenerative diseases (NDs) are protein conformational disorders linked to the propagation of protein misfolding in the brain in a prion-like manner. We discovered that, like prions, misfolded amyloid aggregates of a-synuclein and tau (accumulating, respectively, in Parkinson and Alzheimer disease) spread between neurons in Tunneling Nanotubes (TNTs), a new mechanism of intercellular communication. We propose that TNTs are a major avenue for pathology spreading and thus represent a novel therapeutic target in NDs. By using a multidisciplinary approach and different models (primary neurons, human IPCs, mouse brain slices and zebrafish), we are currently studying the mechanisms of amyloid dissemination and the roles of the lysosomal and autophagic pathways in the progression of these diseases (specifically in cellular models of Parkinson’s and Alzheimer’s).

Furthermore, based on the high frequency of TNTs in non-differentiated cellular states, we hypothesize that TNTs could represent an early feature of cell to-cell communication. Specifically, we propose that in the brain TNTs could serve as a non-synaptic mechanism of communication and be instrumental in early brain development for promoting the emergence of functional mature neuronal networks. We therefore investigate the presence and communicative function of TNTs in the developing brain, by applying a multidisciplinary approach spanning from molecular biology to cellular physiology and a battery of tools relying on cutting edge brain‐mapping methods, computational biology and advanced cellular imaging techniques.

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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 Immunology

Gérard Eberl - Chronic inflammation and neurodegeneration

This unit has demonstrated that the symbiotic microbiota sets the reactivity of the immune system early in life. If this ontogenic regulation fails, individuals develop increased susceptibility to inflammatory pathologies later in life, such as allergy, autoimmunity and cancer. The scientists are now assessing whether this early life education of the immune system by the symbiotic microbiota affects cognition, susceptibility to brain disorders and later life neurodegeneration, and how this pathogenic pathway can be reversed.

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Department of Neurosciences

Aleksandra Deczkowska - Neuro-immune communication throughout life

It is now clear that immune cells play key roles in brain development, homeostasis and disease. Our goal is to dissect the mechanisms of immune-brain cross-talk in physiology and aging and create a strong foundation for future immunotherapy approaches to neurological disease. We specifically focus on the choroid plexus - a site from which circulating immune cells can remotely shape brain function, and microglia - the brain resident macrophages.  Our approach encompasses scRNA-seq and other technologies of genomics, classical tools of immunology, behavioral testing, and everything else that could help us identify the mechanisms of brain-immune communication. 

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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). 

Working also on "neurodegenerative" disease, we have been able to elucidate a role for nAChRs in Alzheimer’s disease (AD), where a “protective” role of nicotine, or even smoking, is debated. In animal models, AD-like pathology is reduced in the absence of the high affinity beta2 nAChR subunit. This is the subunit responsible for the high affinity binding of nicotine, and is “desensitised” in the brains of smokers. This has led to a patent, and a novel strategy to prevent the progression of the disease. 

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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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Christoph Schmidt-Hieber - Cellular and circuit basis of memory formation in health and disease

Forming distinct memories of episodes that closely resemble each other is a critically important task for our brain, as it allows us to distinguish between similar places, events, or people. The input gate to the hippocampus, the “dentate gyrus”, has been suggested to serve this purpose. Intriguingly, during adult life, the dentate gyrus is also one of the few brain regions that is constantly supplied with new neurons. How the activity of new adult-born and mature neurons combines to drive the production and storage of distinct memories represents a new frontier in understanding brain function. This team combines electrophysiological, imaging and behavioural techniques in rodents to explore how this challenge is resolved in the hippocampus and associated brain structures, and how these processes are disrupted in pathological states such as Alzheimer’s Disease.

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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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