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
Duration :2 years
Professor 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.
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.