2008 Passano Laureate & Physician Scientists

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Thomas C. Südhof, M.D

Thomas E. Lloyd, M.D., Ph.D.

 

2008 Passano Laureate

Thomas C. Südhof, M.D., a Professor at the University of Texas Southwestern Medical School, will receive the 2008 Passano Award for his ground-breaking investigation of the biochemical composition of the synapse and his elucidation of the calcium-dependent mechanism of neurotransmitter release, one of the central events in brain function. Neurons communicate at synapses by the controlled release of neurotransmitter from the pre-synaptic cell and the sensing of neurotransmitter by receptors on the surface of the post-synaptic cell. Ever since the pioneering work of Bernard Katz half a century ago, it has been known that neurotransmitters are released in packets and that this release is controlled by calcium entry into the presynaptic neuron. With the visualization of synaptic ultra-structure by electron microscopy, it became apparent that neurotransmitters were stored in presynaptic vesicles and that the release of a packet of neurotransmitter into the synaptic cleft is produced by the fusion of one of these pre-synaptic vesicles with the plasma membrane. Therefore, a central mechanistic question is how presynaptic calcium entry controls vesicle fusion. Twenty years ago, Südhof set out to answer this question by systematically identifying proteins that are enriched in presynaptic vesicles and plasma membrane. This work led to his discovery of the synaptotagmin proteins as the calcium sensors that trigger vesicle fusion. Using a combination of structural biology, electrophysiology, and gene manipulation in mice, Sudhof showed that cooperative calcium binding to the synaptotagmins produces rapid, efficient, and reliable control of neurotransmitter release the three essential attributes of neurotransmission. Südhof also pioneered the identification and analysis of molecules that control the formation of synapses during brain development. In particular, he discovered a cell-surface receptor-ligand system the neurexins and the neuroligins that display enormous structural diversity and that play a central role in initiating the formation of pre- and post-synaptic structures. Südhof's work on the molecular mechanisms of synaptic development and function have broad implications for human health, as current evidence suggests that many neuropsychiatric disorders arise from defects in synaptic development, function, and/or plasticity.