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Institut NeuroMyogène

Institut NeuroMyogène

25 Projects, page 1 of 5
  • Funder: ANR Project Code: ANR-21-CE17-0048
    Funder Contribution: 454,353 EUR

    COQ8A-ataxia is a rare mitochondrial disorder characterized by slowly progressive cerebellar ataxia, combined with variable features including developmental delay, cognitive impairment, epilepsy, dystonia and myopathic features. This rare ataxia is due to loss of function mutations in COQ8A, with no clear genotype-phenotype association. Although its exact biochemical function is unknown, COQ8A has recently been shown to be required to regulate Coenzyme Q biogenesis. CoQ10 functions as an essential component of the mitochondrial respiratory chain, acts as a potent antioxidant, and contributes to membrane structure. Due to the poor bioavailability of CoQ10 to the central nervous system, 50% COQ8A-ataxia patients are non-responders to CoQ10 supplementation. The two main objectives of this proposal are (i) to identify novel therapeutic molecules to treat COQ8A-ataxia using two complementary vertebrate models of the disease and (ii) to determine the pathogenic nature of missense mutation found in COQ8A-ataxia patients. Two main complementary strategies are planned: 1) We will use zebrafish to identify novel molecules for potential therapeutics through a high-throughput screen from FDA-approved drugs, and confirm their effects in murine-derived primary cell models and in vivo mouse models of the disease. 2) We plan to investigate to assess the pathogenicity of patient-derived missense mutations by using a mouse knock-in model and patient-specific allele overexpression in the developing zebrafish.

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  • Funder: ANR Project Code: ANR-19-CE13-0016
    Funder Contribution: 663,727 EUR

    Skeletal muscle growth and repair are critically dependent upon the fusion of nascent myoblasts to pre-existing myofibres. Preliminary data from the participating teams demonstrates that TGFß (SMAD2/3-dependent) signaling acts as a molecular brake on muscle fusion during development of the avian embryo and during muscle regeneration in adult mice. This pathway is therefore the first identified group of molecules acting as inhibitors of fusion. Furthermore, the spectacular hyper-fusion phenotype observed when curbing its signaling in chicken and mouse suggests that tight harnessing of fusion is an unsuspected crucial aspect of muscle formation and repair in vertebrates. In this project, we will identify the intracellular (direct and/or transcriptional) effectors of TGFß signaling and we will test whether mechanical changes at the membrane or in the microenvironment synergize with those effectors to restrain fusion. Ground breaking technologies such as in vivo imaging of fusion, atomic force microscopy, protein micropatterning and optogenetics-mediated activation of signaling will be combined in innovative ways and in different models throughout the project to deliver a unique view of muscle fusion in vertebrates.

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  • Funder: ANR Project Code: ANR-21-CE14-0064
    Funder Contribution: 550,284 EUR

    Muscle dysfunction is implicated in a plethora of human diseases and in sarcopenia, i.e. muscle atrophy with age that constitutes the leading cause of loss of ambulation and independence. This project aims at identifying important pathways for muscle intracellular organization, under physiological and pathological conditions. The function of the muscle fiber (myofiber) is supported by a precise positioning of its organelles and nuclei. Myofibrils generate contractile force under the control of the “excitation-contraction coupling” (ECC) process, based on the interplay between the sarcoplasmic reticulum (SR), a complex network of tubular endoplasmic reticulum (ER), and Transverse (T)-tubules formed by repeated radial invaginations of the plasma membrane. This interplay takes place at specific interactions sites called triads. Centronuclear myopathies (CNMs) are genetically inherited neuromuscular disorders whose prominent histopathological feature is the abnormal myonuclei positioning at the center of myofibers. The main genes involved in CNMs are myotubularin (MTM1), dynamin-2 (DNM2), amphiphysin-2 (BIN1), and ryanodine receptor (RYR1). Of interest, T-tubule organization and function and autophagic process are impacted in several CNMs, impairing muscle homeostasis. However, the connections between myonuclei centralization, altered autophagy and inefficient ECC remain poorly understood. We identified SH3KBP1 (SH3 domain-containing kinase-binding protein 1) as a new factor controlling both myonuclear positioning and T-tubule organization. SH3KBP1 scaffolds perinuclear ER through calnexin binding, and contributes to the formation and maintenance of T-tubules. We also evidenced that this protein binds to DNM2. Thus, these two SH3KBP1 partners could contribute to the correct positioning of myonuclei, organization of triads and to proper function of ECC. In the ATRORESCUE proposal, we aim at characterizing the pathways regulating the organization and functionality of myofibers, focusing on ER and T-tubule remodeling and on associated functions such as autophagy and ECC in physiological or pathological (CNM) contexts. We aim to decipher how the recently identified SH3KBP1 controls these processes in conjunction with MTM1, DNM2 and BIN1. To do so, we will use in vitro cellular assays (cultured myotubes and mature myofibers) and in vivo mouse models (main canonical forms of CNMs linked to mutations in Mtm1, Bin1 or Dnm2) that were validated by the different partners and determine if modulation of these pathways can rescue CNM phenotypes. This proposal is articulated around three complementary axes: 1- ER remodeling and autophagy. We will determine the biological functions of SH3KBP1 and associated proteins in the formation/maintenance of ER, and thus nuclear positioning, through regulation of the autophagic pathway. 2- Triad formation and ECC functionality. We will analyze the impact of SH3KBP1 modulation on the efficiency of T-tubule/triad formation and its repercussions on the ECC. 3- Modulation of SH3KBP1-controlled pathways in mouse models of CNMs. As SH3KBP1 downregulation mimics CNM phenotypes, we will increase its level in three different CNM mouse models through viral transduction and quantify beneficial impacts on muscle functionality with a special focus on myofiber physiology, myonuclei positioning, ER and T-tubule architecture, and ECC efficiency. This collaborative project involves three research groups gathering complementary skills that will allow the study of SH3KBP1-governed pathways involved in the control of the ER, SR, T-tubules and ECC, in vitro and in vivo. Thus, ATRORESCUE will improve our understanding of skeletal muscle function and regulation. Moreover, the validation of SH3KBP1 modulation as a strategy to rescue CNM related phenotypes in vivo may pave the way to treat other neuromuscular diseases and physiological states associated with altered myonuclei location and triad integrity.

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  • Funder: ANR Project Code: ANR-21-CE17-0018
    Funder Contribution: 607,680 EUR

    Idiopathic Inflammatory myopathies (IMs) exhibit a strong Interferon (IFN) signature correlated with the disease severity. Although most patients have muscle defects that resist to treatments, myogenesis has been overlooked. Our data show that: a) IM-derived muscle stem cells (MuSCs, which sustain muscle regeneration), exhibit myogenesis defects in vitro; b) this is recapitulated by treating normal MuSCs with IFN and alleviated with JAK inhibitors (IFN downstream signaling); c) IFNs trigger sequestration of the histone H3.3 chaperone HIRA into specific nucleus bodies (PML NBs), altering its function, histone H3.3 being involved in the regulation of the myogenic transcription factor MyoD. The project will decipher the link between IFN signaling and epigenetic control of myogenesis, to understand the consequences of the IFN response on muscle homeostasis in order to propose a proof of concept of a complementary therapeutic approach to immunosuppressants to prevent muscle sequelae in IMs.

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  • Funder: ANR Project Code: ANR-16-CE16-0023
    Funder Contribution: 564,280 EUR

    This proposal aims at exploring key molecular mechanisms controlling the wiring of neuronal circuits. A first critical step of this developmental program is axon navigation, during which all populations of projection neurons must extend their axons along very specific pathways to connect their proper target territory and start building their synapses. Altering the topography of axon navigation has dramatic consequences, leading to abnormal patterns of neuronal circuits. Functional consequences are obvious in strong cases where circuits are simply not formed or strongly impaired, but increasing contexts are reported, which link more subtle but defective axon navigation to neurological diseases, such autism spectrum disorders. Therefore, understanding the rules of axon navigation is a major goal and an absolute prerequisite for future therapeutic strategies of neuronal circuit repair. Two decades of extensive work established that axon trajectories are controlled by environmental cues. Hence, focal sources and gradients of diffusible and membrane-attached cues having repulsive and attractive properties act in synergy to shape stereotypic axonal pathways. Nevertheless, generating the requested pathway diversity is an incredibly complex task, given that billions of neurons must be connected. How is this diversity encoded remains one of the most fascinating questions in neurodevelopment. Studies that revealed the remarkable potential of axon terminals, the growth cones, to vary their sensitivity to the guidance cues built the current view that diversity might arise from specific spatial and temporal control of guidance receptors and downstream signaling machinery. Despite many advances, information is still sparse on the dynamics of guidance receptors in the growth cones, their cell surface sorting, their spatial distribution and their rearrangement during guidance decisions. This project brings together to highly complementary partners: V. Castellani (Partner 1, Lyon), a neurobiologist with years of experience in the mechanisms of axon guidance; and O. Thoumine (Partner 2, Bordeaux), a biophysicist with strong expertise in single molecule-based super-resolution microscopy applied to growth cones and synaptic receptors. V. Castellani has developed a unique experimental tissue culture set-up in chick embryo for live imaging recapitulating the physiological path-finding of a population of axons, and generated molecular tools to explore at subcellular scales the dynamics of guidance receptors in axons facing key guidance decisions for their navigation. O. Thoumine brings newly developed monomeric ligands conjugated to photostable organic dyes to study the dynamics and nanoscale distribution of those guidance receptors using super-resolution microscopy. The specific biological model is the navigation of commissural axons across the midline separating the two halves sides of the central nervous system, which is one of the most recognized contexts for exploring the modulations of axon responses to guidance cues. Commissural axons are initially attracted towards the midline. After the crossing, they gain responsiveness to local repellents which they did not perceive before. This switch prevents the axons from crossing back and expels them away. Slit proteins, processed into C-ter and N-ter fragments, and the Semaphorin3B (Sema3B) are the major spinal cord midline repellents. The current view supports that at least three repulsive signaling are set after midline crossing: Slit-N acting via Robo receptors, Slit-C acting via PlexinA1 receptor, and Sema3B acting via Neuropilin2/PlexinA1 receptor complex. Using cutting-edge technologies, the consortium will explore the temporal changes of guidance receptor dynamics, the insertion of guidance receptors at the growth cone surface and their spatial compartmentalization in axon subdomains, as well as the mechanisms controlling these spatial and temporal sequences.

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