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Thomas C. Südhof

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Thomas C. Südhof (born December 22, 1955 in Göttingen, Germany) is a biochemist well known for his study of synaptic transmission. Since 1986, Dr. Südhof's research has elucidated many major proteins mediating presynaptic functions. In fact, Sudhof's work has laid the foundation for our current scientific understanding of vesicle-mediated neurotransmitter release, and his continuing work focuses on the specificity of synaptogenesis and synaptic maintenance.

BiographyEdit

A German native, Thomas C. Südhof was born in Göttingen in 1955. Südhof studied medicine at the University of Aachen, Harvard, and then the University of Göttingen where, in 1982, he obtained his M.D. The same year, Südhof finished work on his doctoral thesis, in which he described the structure and function of chromaffin cells, at the Max Planck Institute for Biophysical Chemistry in the lab of Victor P. Whittaker. After a brief postdoctoral fellowship in Whittaker’s lab, Dr. Südhof moved to the United States in 1983, where he began postdoctoral training in the department of molecular genetics at the University of Texas Health Science Center (now the UT Southwestern Medical Center) in Dallas, Texas under the supervision of Michael Stuart Brown and Joseph L. Goldstein.

During his postdoctoral fellowship, Südhof worked to describe the role of the LDL receptor in cholesterol metabolism, for which Brown and Goldstein were awarded the Nobel Prize in Physiology or Medicine in 1985. Südhof finished his postdoctoral training in 1986 and was made an investigator of the Howard Hughes Medical Institute. He was also given his own laboratory at UT Southwestern Medical Center where he focused on the presynaptic neuron for over 20 years.

In 2008, Südhof moved to Stanford University and is currently the Avram Goldstein Professor in the School of Medicine as well as a Professor of Molecular & Cellular Physiology, Psychiatry, and Neurology. During his career, Südhof has defined himself as a clear leader in synaptic research, and his work remains on the frontiers of discovery to this day.

ResearchEdit

Thomas C. Südhof lay the foundations for his scientific career studying the synapse early while studying the mechanisms of neurotransmitter dependent hormone release from neuroendocrine cells for his doctoral thesis at the Max Planck Institute for Biophysical Chemistry. Südhof described the structure and function of chromaffin cells which are responsible for the release of epinephrine, norepinephrine, and endorphins from the medulla of the adrenal gland. Innervated by sympathetic nervous system, chromaffin cells are important in the initiation of the fight or flight response of animals when exposed to threatening stimuli.

After completing his thesis in 1983, Südhof moved to UT Southwestern Medical Center for his postdoctoral training where he began researching in the department of molecular genetics under the supervision of Joseph L. Goldstein and Michael Stuart Brown. While a postdoctoral fellow, Südhof cloned the gene for the low-density lipoprotein receptor and, soon after, was able to explain its transcriptional regulation by cholesterol. When LDL receptors, found concentrated in the liver, bind specific free blood cholesterol, low-density lipoprotein, they are internalized and recycled removing the cholesterol from circulation. This process is a primary source of blood cholesterol regulation and variations in its efficiency were shown to be present in familial hypercholesterolemia. As a result of the discovery, LDL receptor function had also elucidated the principle of receptor-mediated endocytosis—a now universally understood process in cell biology. Goldstein and Brown won the Nobel Prize in Physiology or Medicine for the discovery in 1985.

After finishing postdoctoral training, Thomas Südhof started his own laboratory at UT Southwestern in 1986. Briefly continuing work with Goldstein and Brown, Südhof helped identify a DNA element in the LDL gene that produced sterol mediated end-product repression when inserted in a viral promoter. This domain, known as a sterol regulatory sequence, directly participates in the regulation of sterol biosynthesis. Sterols are a major class of biomolecule and critical for life. Important sterols in humans include cholesterol and steroid hormones. Discovery of sterol regulatory elements and LDL receptor function led to the subsequent development of statin derived cholesterol medications such as atorvastatin (Lipitor)—the top-selling branded pharmaceutical drug in the world in 2008.

As he began working independently, what made Südhof’s research so unique was his focus on the presynaptic neuron. Until Südhof began his work, majority of neuroscience research was aimed at the postsynaptic neuron and its role in learning and memory. Indeed, Thomas Südhof is credited with discovering much of the machinery mediating neurotransmitter release and presynaptic pasticity in his 21 years at UT Southwestern. Südhof began with the discovery of synaptotagmins and their role in neurotransmitter release from the presynaptic neuron. Synaptotagmin, a transmembrane protein found in neurosecretory vesicles, functions as a calcium sensor triggering vesicle fusion and neurotransmitter release. Stimulation of a neuron results in an increase in intracellular calcium concentration. After binding calcium ion to a region in its cytosolic domain, vesicular synaptotagmin promotes quick or slow neurotransmitter release from the presynaptic neuron via interaction with regulatory and fusion related proteins such as members of the SNARE complex. Südhof also discovered RIMs and Muncs (most notably Munc13 and Munc18), soluble proteins which aid in the fusion of neurotransmitter vesicles to the nerve cell membrane and play an important role in synaptic plasticity. In addition, Südhof’s research uncovered the role of many other proteins facilitating vesicle binding, fusion, and resultant neurotransmitter release from the presynaptic neuron, including members of the SNARE complex: synaptobrevin, in the vesicular membrane, syntaxin, in the cell membrane, and SNAP-25, which is tethered to the cytosolic side of the cell membrane via cysteine-linked palmitoyl chains and holds the complex of four helices together. Südhof was also responsible for elucidating the action of tetanus and botulinum toxins, which selectively cleave synaptobrevin and SNAP-25, respectively, inhibiting vesicle fusion with the presynaptic membrane.

More recently, Thomas Südhof’s work has focused on aspects of synaptogenesis and maintenance of the synaptic connection. Südhof discovered neurexins, present on presynaptic neurons, and neuroligins, present on postsynaptic neurons, that come together to form a physical protein bridge across the synapse. The diversity in types of neurexins and neuroligins allows for a variety of unique binding opportunities between neurons and impart a specificity to synaptic connections. In additional studies, Südhof identified mutations in these proteins as a factor in inherited autism.

Thomas Südhof currently continues work on the presynaptic neuron and related topics in his laboratory at Stanford University. Yet to be determined is the mechanism by which neurexins and neuroligins locate each other to form the synapse, their transcriptional regulation, and control of their variability. Südhof’s research has not only given the scientific community a great understanding of the processes underlying synaptic transmission, but has also advanced medical knowledge of mechanisms behind poorly understood diseases such as Alzheimer’s, Schizophrenia, and Autism. He is currently working with a diverse group of researchers at the Howard Hughes Medical Institute to develop mouse models for mutants of synaptic genes. The project aims to drastically advance our understanding of neurological disorders. He also serves on the Research Consortium of Cure Alzheimer's Fund.

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