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Molecular Mechanisms of Neurodegeneration

Final Report Summary - RETROGRADE SIGNALING (Molecular Mechanisms of Neurodegeneration)

The goal of this research is to elucidate key molecular mechanisms of neurodegeneration by revealing the essential communication mechanisms for cell survival and synapse maintenance, between neurons and their environment. Neuronal survival and proper function depend on cell-cell communication mediated by ligand-receptor mechanisms. In this project we seek to define the ligands and receptors facilitating neuron survival and synapse intactness, as well as the molecular mechanisms that regulate this spatial and temporal process. As a diseased model with such alterations we studied ALS Amyotrophic Lateral Sclerosis.
Although the molecular mechanisms for Neuromuscular Junction (NMJ) formation and maintenance are key in many pathological events, including nerve injury or neurodegenerative diseases like ALS, a full understanding of these mechanisms is still lacking. In a recent published paper we built a novel microfluidic platform with motoneuron cell bodies in one compartment and muscle cells in the other, connected via motor axons extending through microgrooves that form functional NMJs. This platform allows precise control, monitoring and manipulation of subcellular microenvironments, thus opening new possibilities for experimental analyses of NMJs. We further utilized this system to directly demonstrate the vulnerability of NMJs to stress, and to track directionality in axon degeneration mechanisms. Using this system we also demonstrated a spatial specificity in the effects of the neurotrophic factor- GDNF and directly tracked for the first time its retrograde transfer from muscle to axons. Our results support a model whereby GDNF facilitates axon growth and innervation only when applied locally in the distal compartment, whereas soma-restricted application of GDNF specifically activates survival pathways (Zahavi et al 2015). In another project, studying mechanisms of axonal transport using the rabies virus as a model, we demonstrated that Rabies Virus hijacks and accelerates the p75NTR (Neurotrophic factor receptor) retrograde transport machinery. A key step in rabies virus fatal infection is to reach the central nervous system by exploiting the cellular trafficking machinery, but the strategy employed by the virus to this end wasn’t fully understood. We used state of the art live cell imaging, including TIRF microscopy, to study the process of virus internalization and long distance transport in primary neuronal cultures grown in microfluidic chambers. Our findings demonstrated for the first time, that the p75 neurotrophin receptor could target rabies virus to a rapid and efficient retrograde axonal transport machinery (Gluska et al 2014). This work suggests an important new paradigm for long distance virus trafficking. We propose a model where rabies virus not only binds p75 to enter the endocytotic and retrograde transport machineries, but also has a positive influence on the kinetics of the transport, thus facilitating its own arrival at the CNS.

Our researches lead to exciting new discoveries that may broadly impact the cell biology and neurobiology communities. First, by understanding the mechanism of spatiotemporal organization of ligands and receptors, and second, by revealing the nature and function of inter- and intracellular signals essential to neuronal health. The expected significance of these experiments is that they reveal fundamental principles of receptor and ligand trafficking mechanisms. This promote basic understanding of how the cell communicates and how a signal arrives to the right place at the right time. Further, as the basic mechanisms of neurodegenerative diseases such as ALS are not yet understood, this project may open up new avenues for future drug development and delivery strategies that will benefit neurodegenerative disease patients by extending their survival and improving their quality of life. To summarize, in aim1 we succeed to develop a novel compartmental microfluidic tool to study basic questions on neuronal communication. In aim 2 we are studying specifically the molecular mechanisms for ligand-receptor spatial temporal trafficking and localizations and its role in neuronal survival and function. In aim 3 we are screening and characterizing RNA, ligands and receptors that play an important role in motor neuron health. In parallel with my research efforts, I also taught both undergraduate and graduate courses for both life sciences and medical students. Further, during the first years of establishing my lab at Tel Aviv University, I was fortunate to obtain a significant number of competitive grants from both national and international research foundations. Among them are grants from the Israel Science Foundation (ISF), the Bi-National US-Israel Science Foundation (BSF), the German-Israel Foundation for scientific research and development (GIF) and a European Research Council (ERC) starting grant. Finally, I am a reviewer for various journals and funding agencies and have been active in organizing committees of both local and international meetings. Thus, I believe that the expected career support and scientific achievement were fully met.