Projects

The purpose of SMA Europe is to provide a framework to stimulate collaboration and accelerate translational research pathways in SMA and promote patient care.

  1. SMA: Mechanisms implicated in the perturbation of the calcium homeostasis and essay of a new therapeutic molecular target

    Principal investigator(s) :
    Professor Lucia Tabares
    Institution :
    University of Seville, Spain
    Grant :
    €99,000
    Year :
    2020
    Duration :
    2 years
    Status :
    Not yet started
    Funding :

    Prof Lucia TabaresProfessor Lucia Tabares from the department of Medical Physiology and Biophysics at the University of Seville in Spain was awarded an SMA Europe grant to study calcium homeostasis in SMN-deficient motor neurons.

    Professor Tabares trained in Electrophysiology and Imaging, from ion channels function to neurotransmission. After medical school, she obtained her Ph.D. through the discovery that adrenal cortical cells are electrically excitable. As a postdoc, she worked on the calcium channels permeation mechanisms with Clay Armstrong at the University of Pennsylvania and the MBL at Woods Hole (USA). During a second postdoc, at the laboratory of David Clapham at the Mayo Clinic (Rochester, MN), she characterised two chloride channels at the cell nucleus membrane. In 2002, she returned to her lab in Spain and started work on SMA. Since then, she has been committed to investigating the neurotransmission defects and the synaptic morphological alterations in this disease and in others mouse models of synaptopathies. In parallel, and in collaboration with Prof. Bill Betz (Univ. of Colorado, USA), she contributed to the understanding of how active zones organisation relates to synaptic transmission regulation. Thet also performed live imaging of the exo-endocytosis dynamics at motor nerve terminals in synaptopHluorin transgenic mice. Professor Tabares was promoted to Professor in 2009.

    Her lab is interested in synaptic function. They investigate the dynamics of quanta release and vesicle replenishment at the motor nerve terminal, as well as the pathogenic mechanisms in diseases where the synapse undergoes degenerative processes such as in SMA. For the study of both synaptic function and dysfunction they combine molecular, electrophysiological, and optical tools and use genetic mouse models. At present, they are investigating exo- and endocytosis in real-time in motor nerve terminals and are studying the role of the mitochondria as a calcium buffer system to modulate cell calcium homeostasis in health and disease.

    Background

    Low levels of the survival motoneuron (SMN) protein causes spinal muscular atrophy (SMA), a devastating neuromuscular disease characterised by motoneuron loss and muscle weakness. What causes the loss of motor neurons is still debated but in SMA, several pieces of evidence signal that cellular calcium (Ca2+) homeostasis is altered. Calcium plays an important role in the ability of motor neurons to transmit signals to muscle cells.

    What is Professor Lucia Tabares proposing to do and why?

    Professor Tabares will investigate to what extend Ca2+ homeostasis is perturbed, the mechanisms implicated, and how Ca2+ dysregulation contributes to the pathogenesis of the disease. She will also test the effectiveness over Ca2+ homeostasis and cell survival of compounds that regulate cell electrical activity. This project will allow Professor Tabares to integrate distinct aspects of the pathophysiology of motoneurons at the level of the cell membrane, the cytosol, and the mitochondria (the cell’s power house) and explore new therapeutic opportunities to protect motor neurons in SMA, in conjunction with SMA-restoring strategies. This has formed the basis of Riluzole in ALS/ MND therapeutics.

  2. Molecular mechanisms of synaptic transmission of the sensory motor-circuit in spinal muscular atrophy

    Principal investigator(s) :
    Dr. Christian Simon
    Institution :
    University of Leipzig, Germany
    Grant :
    €150,000
    Year :
    2020
    Duration :
    2 years
    Status :
    Not yet started
    Funding :

    Dr Christian SimonDr. Christian Simon from Leipzig University is currently a group leader at the Carl-Ludwig-Institute for Physiology as a part of Professor Stefan Hallermann’s laboratory. Dr. Simon’s group studies the mechanisms of neuronal death and dysfunction in motor neuron diseases. During his Masters and PhD, under the supervision of Professor Michael Sendtner at the University of Würzburg, Dr. Simon studied the beneficial effects of neurotrophic factors in SMA mouse models by applying molecular and imaging techniques. In 2012, he joined Prof. George Mentis’ group at Columbia University as a Postdoc, to study neuronal circuitry dysfunction in the spinal cord of SMA mice and stem cell-derived motor neurons. By applying intracellular recordings combined with high resolution microscopy, Dr. Simon could identify novel mechanistic insights of neuronal death and the important contribution of proprioceptive neurons during SMA disease progression. In 2013, he received the Roche Young Investigator Award for neurological research. After his return to Germany in 2017, a grant from the German Research Council allowed him to start his own group in Leipzig.

    Dr. Christian Simon has been granted an SMA Europe award to investigate how proprioceptive synapses degenerate and how their function could be improved, which may aid the discovery of novel therapeutic strategies in humans.

    Background

    Muscle shrinkage and paralysis are the most prominent physical features of SMA patients. Motor neurons that control muscle function are increasingly lost in this disease, which was the main focus of SMA research for decades. However, Dr. Simon and his team recently showed that proprioceptive neurons, which receive spatial information from the muscle and in turn activate motor neurons for proper movement, contribute to SMA immobility.

    What is Dr Simon aiming to do and why?

    In this proposal, Dr. Simon will explore, in mice, whether proprioceptive neurons can be used as a non-invasive, functional biomarker of the disease progression in SMA patients before and during treatment. Furthermore, he will investigate how proprioceptive synapses degenerate and how their function can be improved, in mice.

    How will this work benefit patients?

    Dr. Simon’s work may aid the discovery of novel therapeutic strategies for people living with SMA.

  3. Unravelling the role of Stathmin-2 in SMA as a key a key cause of motor neuron vulnerability and as a therapeutic target

    Principal investigator(s) :
    Dr. Monica Nizzardo
    Institution :
    Neural Stem Cell laboratory, Ospedale Maggiore Policlinico, Milan, Italy
    Grant :
    €150,000
    Year :
    2020
    Duration :
    2 years
    Status :
    Not yet started
    Funding :

    Dr Monica NizzardoDr. Monica Nizzardo, a member of the Neural Stem Cell laboratory at the Ospedale Maggiore Policlinico in Milan, Italy, has been granted an SMA Europe award to look at the potential role of the Stathmin 2 protein in motor neuron degeneration in SMA and its modulation as a therapeutic strategy.

    Background

    To date, the therapies available for SMA aim to restore the levels of SMN1 and thereby, the functionality of the SMN protein encoded by it. Other mechanisms are also altered in this disease and increasing the SMN protein levels alone may not always be sufficient. Another protein, Stathmin 2 (STMN2), is mainly associated with neuronal growth and regeneration. Alterations in its expression or its molecular processing have been described in another neurodegenerative motor neuron disease, amyotrophic lateral sclerosis (ALS). Furthermore, a similar deregulation of STMN2 has been observed in preliminary experiments in human and mouse motor neurons affected by SMA.

    What are the researchers aiming to do and why?

    Dr. Nizzardo will look at the role STMN2 may have in the pathogenesis of SMA. In this project both in vitro and in vivo models of SMA will be used to study the role of STMN2 deregulation in the pathogenesis of the disease and to understand if its modulation can be effective in improving the pathological phenotype of SMA.

    How will this work benefit patients?

    The current clinical trials in SMA which target SMN protein levels are showing great promise. Indeed, one such treatment is now available in Europe. Whilst this represents an important milestone for SMA research it is also clear that these strategies fall significantly short of representing a cure for SMA. Therapies that target other/additional cellular and molecular pathways will likely be required to treat the full range of phenotypes and pathology observed in SMA patients across the life-span. STMN2 may prove to be another potential therapeutic target to treat SMA.